Hormone receptor modulators

Abstract

The present disclosure provides compounds and methods for treating cancer, such as prostate cancer responsive to inhibition and / or degradation of androgen receptor ("AR") polypeptide, and / or breast cancer responsive to inhibition and / or degradation of estrogen receptor ("ER") polypeptide and / or AR polypeptide.

Description

[0001] HORMONE RECEPTOR MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63 / 603,728, filed November 29, 2023. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application. FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant No. HL139860 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD This invention relates to heterocyclic compounds which are, e.g., sex hormone receptor modulators and / or degraders useful in treating various disease states such as cancer (e.g., hormonally-responsive cancer). In one example, the compounds modulate an androgen receptor (“AR”) and are useful in treating prostate cancer and / or benign prostatic hypertrophy (“BPH”) of the prostate. In another example, the compounds either modulate an estrogen receptor (“ER”) or are bi-specific modulators of both the ER and the AR and hence useful in treating breast cancer (e.g., invasive ductal carcinoma or invasive lobular carcinoma). BACKGROUND Cancer is one of the leading causes of death in contemporary society. The numbers of new cancer cases and deaths is increasing each year. Currently, cancer incidence is 454.8 cases of cancer per 100,000 men and women per year, while cancer mortality is 71.2 cancer deaths per 100,000 men and women per year. SUMMARY In some embodiments, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y1, Y2, Y3, R7a, R7b, X1, X2, X3, R2, R3, L3, and R1are as described herein. In some embodiments, the compound of Formula (I) has formula: , or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the present disclosure provides a compound of Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, L1, R4, R5, and R6are as described herein. In some embodiments, the present disclosure provides a compound of Formula (Ib): or a pharmaceutically acceptable salt thereof, wherein R1, L1, R2, L2, X1, R3, R5, and R4are as described herein. In some embodiments, the present disclosure provides a compound of Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, and R6are as described herein. In some embodiments, the present disclosure provides any one of the compounds listed in Table IIa, or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the present disclosure provides any one of the compounds listed in Table IIIa, or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the present disclosure provides any one of the compounds listed in Table A, or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R2b, R3b, R4b, ring A, L1, R1c, R2c, R3c, R4c, and R5care as described herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a method of treating cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, any of the compounds of this disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein R1, R2, X1, X2, X3, R4, R5, and R6are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, X1, X2, R5, R6, R7, and R8are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein X1, R2, R3, R4, R5, R6, R7, and L1are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R6, R7, and L1are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein R2, R3, R5, R6, R7, and L1are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (VII): or a pharmaceutically acceptable salt thereof, wherein X1, X2, RN, R2, R7, and L1are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein X1, X2, RN, R4, R6, R7, and L1are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal a compound of Formula (IX): or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R6, R7, and L1are as described herein. In some embodiments, the method of treating cancer provided in this disclosure includes administering to the mammal any one of the compounds listed in Table B, or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the cancer is prostate cancer, provided that the compound administered to said mammal selectively inhibits and / or degrades an AR polypeptide within the mammal. In some embodiments, said prostate cancer is responsive to degradation of an AR polypeptide or inhibition of activity of an AR polypeptide. In some embodiments, the AR polypeptide comprises an ARv7 isoform. In some embodiments, the mammal is human. In some embodiments, the human is male. In some embodiments, the cancer is breast cancer, provided that (i) the compound administered to said mammal selectively inhibits and / or degrades an ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades an ER polypeptide and an AR polypeptide within the mammal. In some embodiments, the breast cancer is responsive to degradation or inhibition of activity of an ER polypeptide, or responsive to degradation or inhibition of activity of an ER polypeptide and an AR polypeptide. In some embodiments, the AR polypeptide comprises an ARv7 isoform. In some embodiments, the mammal is human. In some embodiments, the human is female. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG.1 contains experimental data showing that exemplified compound K216- 7800 reduced AR and ARv7 protein in 22RV1 cells. FIG.2 contains experimental data showing that exemplified compound K216- 1659 reduced AR and ARv7 protein and their downstream target PSA. FIG.3 shows that genes activated by ARv7, such as NUP210, PSA and Tmprss2 are dose dependently suppressed by K216-1659. FIG.4A contains experimental data showing killing efficacy for exemplified compound K216-1659 in proliferation assay against 22RV1 and PC3 cells. FIG.4B contains experimental data showing killing efficacy for exemplified compound enzalutamide in proliferation assay against 22RV1 and PC3 cells. FIG.4C contains experimental data showing that exemplified compound K216- 1659 reduces 22RV1 proliferation. FIG.4D contains experimental data showing that exemplified compound K216- 1659 did not inhibit proliferation in non-prostate cancer cell lines. FIG.5A contains experimental data showing that both the exemplified compound K216-1659 and the AR antagonist enzalutamide demonstrated comparable potency in reducing proliferation of wild-type AR driven prostate cancer cells. FIG.5B contains experimental data showing that the exemplified compound K216-1659 time dependently reduced proliferation of prostate cancer VCaP cells. FIG.6 contains experimental data showing that exemplified compounds K216- 1659 and K216-0499 dose dependently decrease a similar set of AR related genes. FIG.7 contains experimental data showing that exemplified compound K216- 1659 and enzalutamide have similar profile in regulating AR pathway. FIG.8 contains domain structure of the Estrogen Receptor (ER) protein. The ligand binding domain (LBD) is on the carboxy-terminus of the protein. In contrast, our molecules bind to the first 300 amino acids of the protein, which represent the N- terminus of the molecule. FIG.9 contains a line plot showing that an ER-active compound (denoted as CPd1) directly binds to the N-terminal domain of the ER. Assay reflects temperature shift in the cellular thermal shift assay (CETSA) indicative of ligand-protein interaction. FIG.10 contains images showing that test compounds bind outside the traditional binding site for therapeutics. Here, test compound (denoted as Cpd1) is compared to a previously published small molecule ER PROTAC compound. Under standard conditions, both compounds degrade the ER, as evident by Western blot (top). However, in the presence of molar excess of tamoxifen, the PROTAC molecule is no longer effective, while the test compound remains active as a protein degrader. This is consistent with the molecule binding outside the traditional LBD. FIG.11 shows the degradation curves generated at 24h for compound ZE76-0978 and a control compound (AR PROTAC ARv-766). The compounds were tested in a 22RV1 cell with CRISPR HiBiT tag on ARv7 protein, and a C4-2 cell with CRISPR HiBiT tag on AR protein. FIG. 12A shows the results of testing compound ZE76-0978 in C4-2 and 22RV1 cells and measuring the downstream gene expression profiles. For the test, C4-2 and 22RV1cells plated in 12 well plates were treated with compound ZE76-0978 for 18h (0-10 M). Cells were collected for RNA isolation followed by QPCR. Genes activated by AR, such as IGF1, KLK2, PSA and Tmprss2, were dose dependently suppressed by ZE76-0978. FIG 12B shows the result of processing 22RV1 cells treated with compound ZE76- 0978 for RNA sequences. ~1000 known AR regulated genes were found to be affected by ZE76-0978. FIG 13 shows the results of testing compound ZE76-0978 in various proliferation assays. Three ARv7 / AR driven prostate cells (22RV1, LNCAP, C4-2), one non-AR driven prostate cell (PC3), and five control cells (Astrocytes, PBMC, Fibroblast, RPTEC, Beas2B) were plated in white Nunc 384 before addition of the compound.7 days later, cells were assayed using CellTiter-Glo to evaluate compound killing efficacy. ZE76-0978 showed potent proliferation inhibition in ARv7 / AR driven prostate cancer cells but not in all other control cell lines. FIG 14 shows the results of testing several exemplified compounds and three positive controls (ARV-766, BMS-986365 and Apalutamide) in a patient derived organoid model (PR9582B, CrownBio). Cells were grown in a clear bottom 384 well plate with compound treatment for 7 days. Cells were assayed using CellTiter-Glo to evaluate the killing efficacy of the compound. Absolute IC50, Imax and kill curve AUC were measured and are shown in Figure.14. DETAILED DESCRIPTION Prostate cancer Without being bound by any theory or speculation, it is believed that growth of prostate cancer is driven by androgen receptor (AR) dependent proliferation. The normal androgen receptor is a transcription factor whose activity is regulated by binding its ligand (e.g., androgens like testosterone). Patients with prostate cancer are initially treated with anti-androgen therapies. Most, if not all, patients on these therapies develop resistance to these approaches. A very common molecular event resulting from the resistance is the development of a mutant form of the androgen receptor termed androgen receptor splice variant 7 (“ARv7”). This form of AR no longer requires androgens to activate its transcriptional activity. At present there are few targeted therapies that can address patients who express ARv7, which is often associated with what is known as castration-resistant prostate cancer. The present disclosure provides organic compounds that can inhibit the activity of wild-type AR and / or mutant forms of AR, and / or induce the molecular degradation of wild-type AR and / or mutant forms of AR. Such mutant forms may include, for example, forms with point mutations, genetic deletions, or genetic rearrangements of wild-type AR. In some embodiments, the present disclosure provides organic compounds that can inhibit the activity of AR and / or ARv7, and / or induce the molecular degradation of AR and ARv7 and are effective at inhibiting the growth of prostate cancer cell lines. Accordingly, in some embodiments, the present disclosure provides therapeutic compounds (e.g., therapeutic organic compounds such as those described herein) having the ability to inhibit and / or degrade AR protein (e.g., isoform ARv7 of AR protein) within cells (e.g., cancer cells such as prostate cancer cells), formulations and compositions containing these therapeutic compounds, as well as methods for treating mammals (e.g., humans) having a cancer (e.g., prostate cancer) responsive to degradation of AR or a cancer (e.g., prostate cancer) where degradation of AR leads to reduced proliferation of the cancer cells. In some embodiments, the present disclosure provides a method for inhibiting or degrading (e.g., decreasing level of) an AR polypeptide within a cell (e.g., cancer cell such as prostate cancer cell) by contacting the cell with a therapeutic compound as described herein, or a pharmaceutically acceptable salt thereof. The decrease in AR polypeptide level (degradation) in the cell can be compared to the AR polypeptide levels in the cell prior to the contacting step. In some embodiments, the contacting is carried out in vitro, in vivo, or ex vivo. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a prostate cancer cell (e.g., prostate cancer cell responsive to AR inhibition or degradation or a prostate cancer cell in which proliferation in inhibited by degradation or inhibition of AR polypeptide). In some embodiments, the AR polypeptide is a wild type isoform. In some embodiments, the AR polypeptide is an ARv7 isoform. In some embodiments, the therapeutic compounds of this disclosure selectively degrade wild type isoform of AR as compared to ARv7 isoform, or any other isoform of AR polypeptide. In some embodiments, the therapeutic compounds of this disclosure selectively degrade ARv7 isoform of AR as compared to wild type isoform, or any other isoform of AR polypeptide In some embodiments, the compound is about 100-fold, about 50-fold, or about 10-fold selective to ARv7 isoform as compared to any other isoform of AR polypeptide. In some embodiments, the method comprising simultaneously degrading ARv7 isoform and AR wild type isoform. In some embodiments, the method for inhibiting or degrading (or decreasing level of) an AR polypeptide in a cell (e.g., e.g., cancer cell such as prostate cancer cell) can be performed in vitro. For example, one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, can be added to a cell culture containing cancer cells (e.g., prostate cancer cells obtained from a human male) to inhibit or degrade AR polypeptide within those cells. In some embodiments, the method for inhibiting or degrading (or decreasing the level of) an AR polypeptide in a cell can be performed in vivo. For example, the one or more therapeutic compounds described herein, or a pharmaceutically acceptable salt thereof, can be administered to a mammal (e.g., a human) to inhibit or degrade the AR polypeptide within the cells (e.g., cancer cells) within that mammal. In some embodiments, the present disclosure provides a method for inhibiting or degrading (or decreasing the level of) an AR polypeptide in a cell (e.g., cancer cell such as prostate cancer cell) of the subject, the method comprising administering to the subject (e.g., the subject in need of cancer treatment, such as a human male subject in need to prostate cancer treatment) a therapeutically effective amount of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, the present disclosure provides a method for treating cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of any one of the compounds presented herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some cases, the cancer is responsive to inhibition and / or degradation of AR polypeptide (e.g., isoform ARv7, a wild-type isoform of AR, or both). In some cases, the cancer is associated with overexpressed or constitutively activated AR polypeptide (e.g., isoform ARv7, a wild-type isoform of AR, or both). In some embodiments, inhibition or degradation or AR polypeptide in a cancer cell results in inhibiting of proliferation or cancer cell death. In some embodiments, the cancer is a prostate cancer. Suitable examples of prostate cancer include adenocarcinoma of the prostate, transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, and small cell prostate cancer. In some embodiments, the prostate cancer is castration resistant. In some embodiments, the prostate cancer is not castration resistant. In some embodiments, the prostate cancer is responsive to AR protein inhibition or degradation (e.g., inhibition or degradation of AR protein results in inhibited proliferation of prostate cancer cells and / or prostate cancer cell death). In some embodiments, the prostate cancer is responsive to androgen antagonist / inhibitor chemotherapy. In some embodiments, the prostate cancer is not responsive to androgen antagonist / inhibitor chemotherapy. In some embodiments, the condition is benign prostatic hypertrophy, a benign condition caused by non-malignant growth of the prostate. In some embodiments, a mammal in need of cancer treatment is a human. For example, e.g., in case where cancer is a prostate cancer, the mammal is a human male. In some embodiments, the human male is castrated. In some embodiments, the human male is not castrated. In some embodiments, the human male mammal subject underwent or concurrently undergoes an androgen antagonist / inhibitor chemotherapy Breast cancer Without being bound by any theory or speculation, it is believed that growth of breast cancer is driven by estrogen receptor (“ER”) dependent proliferation and / or ER and AR dependent proliferation. The present disclosure provides organic compounds that can inhibit the activity of ER and / or AR, and / or induce the molecular degradation of ER and AR (including any isoforms of these receptors) and is effective at inhibiting the growth of breast cancer cells. Such isoforms forms may include, for example, forms with point mutations, genetic deletions, or genetic rearrangements of wild-type ER and / or AR. Accordingly, in some embodiments, the present disclosure provides therapeutic compounds (e.g., therapeutic organic compounds such as those described herein) having the ability to inhibit and / or degrade ER protein within cells (e.g., cancer cells such as breast cancer cells), formulations and compositions containing these therapeutic compounds, as well as methods for treating mammals (e.g., humans) having a cancer (e.g., breast cancer) responsive to degradation of ER or a cancer (e.g., breast cancer) where degradation of ER leads to reduced proliferation of the cancer cells. In some embodiments, the present disclosure provides a method for inhibiting or degrading (e.g., decreasing level of) an ER polypeptide within a cell (e.g., cancer cell such as breast cancer cell) by contacting the cell with a therapeutic compound as described herein, or a pharmaceutically acceptable salt thereof. The decrease in ER polypeptide level (degradation) in the cell can be compared to the ER polypeptide levels in the cell prior to the contacting step. In some embodiments, the contacting is carried out in vitro, in vivo, or ex vivo. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a breast cancer cell (e.g., breast cancer cell responsive to ER inhibition or degradation or a breast cancer cell in which proliferation in inhibited by degradation or inhibition of ER polypeptide). In some embodiments, the present disclosure provides a method for inhibiting or degrading (e.g., decreasing level of) an ER polypeptide and / or AR polypeptide within a cell (e.g., cancer cell such as breast cancer cell) by contacting the cell with a therapeutic compound as described herein, or a pharmaceutically acceptable salt thereof. The decrease in ER polypeptide level and / or AR polypeptide level (degradation) in the cell can be compared to the ER polypeptide levels and / or AR polypeptide levels in the cell prior to the contacting step. In some embodiments, the contacting is carried out in vitro, in vivo, or ex vivo. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a breast cancer cell (e.g., breast cancer cell responsive to ER and / or AR inhibition or degradation or a breast cancer cell in which proliferation is inhibited by degradation or inhibition of ER polypeptide and / or AR polypeptide). In some embodiments, the method for inhibiting or degrading (or decreasing level of) an ER polypeptide in a cell (e.g., cancer cell such as breast cancer cell) can be performed in vitro. For example, one or more compounds provided herein, or a pharmaceutically acceptable salts thereof, can be added to a cell culture containing cancer cells (e.g., breast cancer cells obtained from a human female having the cancer of the breast) to inhibit or degrade ER polypeptide within those cells. In some embodiments, the method for inhibiting or degrading (or decreasing the level of) an ER polypeptide in a cell can be performed in vivo. For example, the one or more therapeutic compounds described herein, or a pharmaceutically acceptable salt thereof, can be administered to a mammal (e.g., a human) to inhibit or degrade the ER polypeptide within the cells (e.g., cancer cells) within that mammal. In some embodiments, the present disclosure provides a method for inhibiting or degrading (or decreasing the level of) an ER polypeptide in a cell (e.g., cancer cell such as breast cancer cell) of the subject, the method comprising administering to the subject (e.g., the subject in need of cancer treatment, such as a human female subject in need to breast cancer treatment) a therapeutically effective amount of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, the present disclosure provides a method for treating cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of any one of the compounds presented herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some cases, the cancer is responsive to inhibition and / or degradation of ER polypeptide or both the ER and the AR polypeptide. In some cases, the cancer is associated with overexpressed or constitutively activated ER polypeptide. In some embodiments, inhibition or degradation or ER polypeptide in a cancer cell results in inhibiting of proliferation or cancer cell death. In some embodiments, the cancer is a breast cancer. Suitable examples of breast cancer include ductal or lobular carcinoma, invasive breast cancer, triple-negative breast cancer, inflammatory breast cancer, Paget disease of the breast, angiosarcoma, phyllodes tumor, and metastatic breast cancer. In some embodiments, the breast cancer is responsive to ER protein inhibition or degradation (e.g., inhibition or degradation of ER protein results in inhibited proliferation of breast cancer cells and / or breast cancer cell death), or ER and AR protein inhibition or degradation. In some embodiments, the breast cancer is responsive to estrogen antagonist / inhibitor chemotherapy. In some embodiments, the breast cancer is not responsive to estrogen antagonist / inhibitor chemotherapy. In some embodiments, a mammal in need of cancer treatment is a human. For example, e.g., in case where cancer is a breast cancer, the mammal is a human female. In some embodiments, the human female mammal subject underwent or concurrently undergoes an estrogen antagonist / inhibitor chemotherapy Additional examples of cancer Suitable additional examples of cancers treatable by the therapeutic compounds of this disclosure include sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, lung cancer, bronchogenic carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, cancer of the esophagus, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, cancer of the stomach, carcinoma, lymphoma, leiomyosarcoma, cancer of the pancreas, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, cancer of the small bowel, adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, cancer of the large bowel or colon, tubular adenoma, villous adenoma, hamartoma, leiomyoma, genitourinary tract cancer , cancer of the kidney adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia, cancer of the bladder, cancer of the urethra, squamous cell carcinoma, transitional cell carcinoma, cancer of the prostate, cancer of the testis, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma, liver cancer, hepatoma hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma giant cell tumor, nervous system cancer, cancer of the skull, osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, cancer of the meninges meningioma, meningiosarcoma, gliomatosis, cancer of the brain, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancer of the spinal cord, neurofibroma, meningioma, glioma, sarcoma, gynecological cancer, cancer of the uterus, endometrial carcinoma, cancer of the cervix, cervical cancer, cervical carcinoma, pre tumor cervical dysplasia, cancer of the ovaries, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli Leydig cell tumor, dysgerminoma, malignant teratoma, cancer of the vulva, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, cancer of the vagina, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, cancer of the fallopian tubes, hematologic cancer, cancer of the blood, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), Waldenstrom's macroglobulinemia, skin cancer, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, adrenal gland cancer, and neuroblastoma. In some embodiments, the human subject (e.g., male subject or female subject) is from about 18 to about 75 years old, or from 35 to about 75 years old, or from about 45 to about 75 years old, or from about 55 to about 75 years old. In some embodiments, the method includes a step of identifying a mammal in need of cancer treatment (e.g., by diagnosing the mammal with cancer or by identifying the mammal already diagnosed with cancer). The diagnosis can be performed by a lab technician, a diagnostician, a treating physician, a primary care physician, or a specialty physician such as an oncologist. The diagnosis can be performed on the basis of laboratory tests (e.g., MRI imaging or testing a specimen obtained from the mammal for a cancer biomarker), a clinical observation, or both. Therapeutic compounds Compound of Formula (I): In some embodiments, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR2a; X2is selected from N and CR2a; X3is selected from N and CR4; provided that at least one of X1, X2, and X3is N; R2, R2a, R3, and R4are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; and L1is selected from C(=O)NH, NHC(=O), NHC(=O)NH, and NHC(=O)O; or L1is absent; R1is selected from C1-6alkyl and Cy1, wherein said C1-6alkyl is optionally substituted with C1-6alkoxy, C1-6alkylamino, or Cy1; each Cy1is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with RCy1; and each RCy1is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, and carboxy; each Y1is independently selected from O, S, and NH; each Y2is independently selected from N and CR6b; each Y3is independently selected from N and CR5b; R5a, R5b, R6a, R6b, R7a, and R7bare each independently selected from H, NO2, OH, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, the compound of Formula (I): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (I) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (Ia) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (I) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, the compound of Formula (I) has formula: or a pharmaceutically acceptable salt or N-oxide thereof, wherein: X1selected from N and CR2a; R1is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; R2, R2a, R3, and R4are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; and R5a, R5b, R6a, R6b, R7a, and R7b, are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene. In some embodiments, X1is N. In some embodiments, X1is CR2a. In some embodiments, X2is N. In some embodiments, X2is CR2a. In some embodiments, X3is N. In some embodiments, X3is CR2a. In some embodiments, R2, R2a, R3, and R4are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R2a, R3, and R4are each H. In some embodiments, at least one of R2, R2a, R3, and R4is independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NHC(=O). In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is NHS(=O)2NH. In some embodiments, L1is NHS(=O)2O. In some embodiments, L1is absent. In some embodiments, R1is C1-6alkyl. In some embodiments, R1is C1-6alkyl substituted with C1-6alkoxy, C1-6alkylamino, or Cy1. In some embodiments, R1is C1-6alkyl substituted with Cy1. In some embodiments, Cy1is C6-10aryl optionally substituted with RCy1. In some embodiments, Cy1is 5-14 membered heteroaryl optionally substituted with RCy1. In some embodiments, Cy1is 4-10 membered heterocycloalkyl optionally substituted with RCy1. In some embodiments, RCy1is selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and carboxy. In some embodiments, Y1is O. In some embodiments, Y1is S. In some embodiments, Y1is NH. In some embodiments, Y2is N. In some embodiments, Y2is CR6b. In some embodiments, Y3is N. In some embodiments, Y3is CR5b. In some embodiments, R5a, R5b, R6a, R6b, R7a, and R7bare each independently selected from H, NO2, OH, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R5a, R5b, R6a, R6b, R7a, and R7bis selected from NO2, OH, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R5a, R5b, R6a, R6b, R7a, and R7bare each H. In some embodiments, the compound of Formula (I) is selected from any one of the following compounds provided in Table I: Table I or a pharmaceutically acceptable salt thereof. Compounds of Formula (Ia): In some embodiments, the present disclosure provides a compound of Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R1and R2are each independently selected from C1-3haloalkyl, CN, and Cy1; each Cy1is selected from furanyl and phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene; provided that only one of R1and R2is Cy1; L1is C(=O)NH or L1is ablsent; R4is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; and R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, the compound of Formula (Ia): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Ia) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (Ia) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Ia) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, R1is Cy1. In some embodiments, R2is Cy1. In some embodiments, R1is C1-3haloalkyl and R2is Cy1. In some embodiments, R1is CN and R2is Cy1. In some embodiments, R1is Cy1and R2is C1-3haloalkyl. In some embodiments, R1is Cy1and R2is CN. In some embodiments, Cy1is furanyl, substituted with 1, 2, or 3 substituents independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy1is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, L1is C(=O)NH. In some embodiments, L1is absent. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-6alkyl substituted with C1-6alkoxy. In some embodiments, R4is C1-6alkyl substituted with C1-6alkylamino. In some embodiments, R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R3, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy,and C1-6haloalkoxy. In some embodiments, R3, R5, and R6are each H. In some embodiments, the compound of Formula (Ia) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) is selected from any one of the following compounds: Table Ia or a pharmaceutically acceptable salt thereof. Compound of Formula (Ib): In some embodiments, the present disclosure provides a compound of Formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and R2a; L1is NHC(=O) or L1is absent; L2is NHC(=O) or L2is absent; R1and R2are each independently a furanyl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, or HO- C1-3alkylene; R4is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; and R2a, R3, and R5are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, the compound of Formula (Ib): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Ib) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (Ib) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Ib) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is R2a. In some embodiments, L1is NHC(=O). In some embodiments, L1is absent. In some embodiments, L2is NHC(=O). In some embodiments, L2is absent. In some embodiments, R1is furanyl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, or HO-C1-3alkylene. In some embodiments, R2is furanyl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, or HO-C1-3alkylene. In some embodiments, R1is furanyl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, or C1-6haloalkoxy. In some embodiments, R2is furanyl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, or C1-6haloalkoxy. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-6alkyl substituted with C1-6alkoxy. In some embodiments, R4is C1-6alkyl substituted with C1-6alkylamino. In some embodiments, R2a, R3, and R5are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2a, R3, and R5is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2a, R3, and R5are each H. In some embodiments, the compound of Formula (Ib) has any one of the following formulae: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ib) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ib) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ib) is selected from any one of the following compounds listed in Table Ib: Table Ib or a pharmaceutically acceptable salt thereof. Compound of Formula (Ic): In some embodiments, the present disclosure provides a compound of Formula (Ic): or a pharmaceutically acceptable salt or N-oxide thereof, wherein: R1and R2are each independently a phenyl, optionally substituted with 1, 2, or 3 independently selected RCy1; each RCy1is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene; R4is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; and R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, the compound of Formula (Ic): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Ic) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (Ic) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Ic) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, R1is phenyl, optionally substituted with 1, 2, or 3 independently selected RCy1. In some embodiments, R2is phenyl, optionally substituted with 1, 2, or 3 independently selected RCy1. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, RCy1is selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-6alkyl substituted with C1-6alkoxy. In some embodiments, R4is C1-6alkyl substituted with C1-6alkylamino. In some embodiments, R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R3, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R3, R5, and R6are each H. In some embodiments, the compound of Formula (Ic) is selected from any one of the following compounds: Table Ic or a pharmaceutically acceptable salt thereof. Compounds of Formula (Id) In some embodiments, the present disclosure provides a compound of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR1a; X2is selected from N and CR2a; X3is selected from N and CR3; provided that at least one of X1, X2, and X3is N; R1a, R2a, R3, R4, R5, and R6are each independently selected from H, Cy1, halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRc1Rd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7; each R7is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; each RCy1is independently selected from halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl ,4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8; each R8is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; R1and R2are each independently selected from R9and S(O)2R9; each R9is independently selected from CN, C1-6haloalkyl, and Cy2; each Cy2is independently selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; each R10is independently selected from halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11; each R11is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; each Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and each Rgis independently selected from OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5- 10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, (C=O)C6-10aryl, (C=O)C3-10cycloalkyl, (C=O)5-10 membered heteroaryl, (C=O)4-10 membered heterocycloalkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (Id): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Id) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (Id) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (Id) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is CR1a. In some embodiments, X2is N. In some embodiments, X2is CR2a. In some embodiments, X3is N. In some embodiments, X3is CR3. In some embodiments, R1a, R2a, R3, R4, R5, and R6are each independently selected from H, Cy1, halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRc1Rd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7. In some embodiments, R1a, R2a, R3, R4, R5, and R6are each independently selected from H, Cy1, halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6alkyl is optionally substituted with 1 or 2 substituents independently selected from R7. In some embodiments, R1ais selected from H, Cy1, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R2ais selected from H, Cy1, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R3is selected from H, Cy1, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R4is selected from H, Cy1, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R5is selected from H, Cy1, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R6is selected from H, Cy1, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R3, R5, and R6are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R3, R5, and R6are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R3, R5, and R6are each selected from H and C1-6alkyl. In some embodiments, R3, R5, and R6are each H. In some embodiments, R4is selected from Cy1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, and S(O)2NRc1Rd1. In some embodiments, R4is selected from Cy1, C(O)NRc1Rd1, and C(O)ORa1. In some embodiments, R4is Cy1(e.g., 1,2,4-triazolyl, tetrazolyl, oxazolyl, or 1,2,4-oxadiazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy1). In some embodiments, R4is C(O)NRc1Rd1. In some embodiments, R4is a group of formula: In some embodiments, R4is C(O)ORa1(e.g., R1is H or C1-6alkyl). In some embodiments, R3, R4, and R6are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, ORa1, C(O)ORa1, and NRc1Rd1, wherein said C1-6alkyl is optionally substituted with a substituent selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R3, R4, and R6are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R3, R4, and R6are each selected from H and C1-6alkyl. In some embodiments, R3, R4, and R6are each H. In some embodiments, R5is selected from Cy1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, and S(O)2NRc1Rd1. In some embodiments, R5is selected from Cy1, C(O)NRc1Rd1, and C(O)ORa1. In some embodiments, R5is Cy1(e.g., 1,2,4-triazolyl, tetrazolyl, oxazolyl, or 1,2,4-oxadiazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy1). In some embodiments, R5is C(O)NRc1Rd1. In some embodiments, R5is a group of formula: In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, Rc1and Rd1are each independently selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, and C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with a substituent selected from OH, thio, C1-6alkoxy, C1-6thialkoxy, C1-6haloalkoxy, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, Rc1and Rd1are each independently selected from H, C1-6alkyl, and C2-6alkynyl, wherein said C1-6alkyl is optionally substituted with a substituent selected from OH, C1-6alkoxy, and di(C1-6alkyl)amino. In some embodiments, Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1 or 2 substituents independently selected from Rg. In some embodiments, Rc1is H and Rd1is C2-6alkynyl. In some embodiments, Rc1and Rd1together with the N atom to which they are attached form a ring selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, and azepanyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Rg. In some embodiments, Rc1and Rd1together with the N atom to which they are attached form a piperazinyl ring, optionally substituted with 1 or 2 Rg. In some embodiments, Rc1and Rd1together with the N atom to which they are attached form a piperazinyl ring of formula: . In some embodiments, Ra1is selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, and C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with a substituent selected from OH, thio, C1-6alkoxy, C1-6thialkoxy, C1-6haloalkoxy, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, Ra1is selected from H, C1-6alkyl, and C2-6alkynyl, wherein said C1-6alkyl is optionally substituted with a substituent selected from OH, C1-6alkoxy, and di(C1-6alkyl)amino. In some embodiments, Ra1is selected from H and C1-6alkyl. In some embodiments, Ra1is C2-6alkynyl. In some embodiments: Rc1and Rd1are each independently selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, and C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with a substituent selected from OH, thio, C1-6alkoxy, C1-6thialkoxy, C1-6haloalkoxy, amino, C1-6alkylamino, and di(C1-6alkyl)amino; and Ra1is selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, and C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with a substituent selected from OH, thio, C1-6alkoxy, C1-6thialkoxy, C1-6haloalkoxy, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments: Rc1and Rd1are each independently selected from H, C1-6alkyl, and C2-6alkynyl, wherein said C1-6alkyl is optionally substituted with a substituent selected from OH, C1-6alkoxy, and di(C1-6alkyl)amino; and Ra1is selected from H, C1-6alkyl, and C2-6alkynyl, wherein said C1-6alkyl is optionally substituted with a substituent selected from OH, C1-6alkoxy, and di(C1-6alkyl)amino. In some embodiments, Rb1is selected from C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with 1 or 2 independently selected Rg. In some embodiments, Rb1is C1-6alkyl, optionally substituted with Rg. In some embodiments, Cy1is C6-10aryl, optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is 4-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is 5-10 membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is 5-6 membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is 5-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4- oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, Cy1is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, and 1,2,4-oxadiazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy1. In some embodiments, RCy1is selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with 1 or 2 independently selected R8. In some embodiments, RCy1is C1-6alkyl, optionally substituted with R8. In some embodiments, R8is selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R8is selected from OH, thio, C1-6alkoxy, C1-6thialkoxy, C1-6haloalkoxy, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, R1is R9. In some embodiments, R1is S(O)2R9. In some embodiments, R2is R9. In some embodiments, R2is S(O)2R9. In some embodiments, R1is R9and R2is R9. In some embodiments, R1is R9and R2is S(O)2R9. In some embodiments, R1is S(O)2R9and R2is R9. In some embodiments, R9is C1-6haloalkyl. In some embodiments, R9is CF3. In some embodiments, R9is CN. In some embodiments, R9is Cy2. In some embodiments, R9is selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R9is C6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R9is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R9is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R1and R2are each independently selected from C1-6haloalkyl, C6-10aryl, and 5-10 membered heteroaryl, wherein said C6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 independently selected from R10. In some embodiments, R1and R2are each independently a C6-10aryl, optionally substituted with 1 or 2 independently selected from R10. In some embodiments: R1is 5-10 membered heteroaryl, optionally substituted with 1 or 2 independently selected from R10; and R2is C6-10aryl, optionally substituted with 1 or 2 independently selected from R10. In some embodiments: R1is C6-10aryl, optionally substituted with 1 or 2 independently selected from R10; and R2is 5-10 membered heteroaryl, optionally substituted with 1 or 2 independently selected from R10. In some embodiments: R1is C1-6haloalkyl; and R2is C6-10aryl, optionally substituted with 1 or 2 independently selected from R10. In some embodiments: R1is C1-6haloalkyl; and R2is 5-10 membered heteroaryl, optionally substituted with 1 or 2 independently selected from R10. In some embodiments: R1is C6-10aryl, optionally substituted with 1 or 2 independently selected from R10; and R2is C1-6haloalkyl. In some embodiments, R10is selected from halo, CN, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, R10is selected from halo, CN, NRc1Rd1, NRc1C(O)Rb1, and S(O)2Rb1. In some embodiments, Rgis selected from OH, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, the compound of Formula (Id) is selected from any compound provided in Table I, Ia, Ib, Ic, and any of the following compounds provided in Table Id: Table Id

[0002] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Id) is selected from any one of the following compounds of Table Ie: Table Ie Compounds of Formula (II) In some embodiments, the present disclosure provides a compound of Formula (II):

[0003] or a pharmaceutically acceptable salt or N-oxide thereof, wherein: X1is selected from N and CR4a; X2is selected from C(=O), CHOH, CH2, NRNC(=O), C(=O)NRN, and NRN; RNis selected from H and C1-3alkyl; and R1, R2, R3, R4, R4a, R5, R6, R7, and R8are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino. In some embodiments, the compound of Formula (II): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (II) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (II) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (II) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, the compound of Formula (II) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, X1is N. In some embodiments, X1is CR4a. In some embodiments, X2is C(=O). In some embodiments, X2is CHOH. In some embodiments, X2is CH2. In some embodiments, X2is NRNC(=O). In some embodiments, X2is NHC(=O). In some embodiments, X2is C(=O)NRN. In some embodiments, X2is C(=O)NH. In some embodiments, X2is NRN. In some embodiments, X2is NH. In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, R1, R2, R3, R4, R4a, R5, R6, R7, and R8are each independently selected from H, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R1is halo. In some embodiments, R1is Cl. In some embodiments, R1is F. In some embodiments, R2is Cl. In some embodiments, R2is F. In some embodiments, R1is CF3. In some embodiments, R2is CF3. In some embodiments, R1is halo and R2is halo. In some embodiments, the compound of Formula (II) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides any of the compounds listed in Table IIa, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is selected from any of the compounds provided in Table IIa and any one of the compounds provided in Table IIb:

[0004] or a pharmaceutically acceptable salt thereof. Compounds of Formula (III) In some embodiments, the present disclosure provides a compound of Formula (III):

[0005] or a pharmaceutically acceptable salt thereof, wherein: Ra1is selected from H and C1-3alkyl; ring A is selected from imidazolidinone, piperazine, imidazole, oxazolidinone, thiazole, and oxazole, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O), CH2, and NH; or L1is absent; R1b, R2b, R3b, and R4bare each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R3cis halo; R4cis halo; and R1c, R2c, and R5care each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (III): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (III) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (III) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (III) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, Ra1is H. In some embodiments, Ra1is C1-3alkyl. In some embodiments, ring A is imidazolidinone, optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, ring A is piperazine, optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, ring A is imidazole, optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, ring A is oxazolidinone, optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, ring A is thiazole, optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, ring A is oxazole, optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, ring A is selected from any one of the following moieties: wherein either indicates a point of attachment to L1. In some embodiments, L1is C(=O). In some embodiments, L1is CH2. In some embodiments, L1is NH. In some embodiments, L1is absent. In some embodiments, R1b, R2b, R3b, and R4bare each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R3cis halo. In some embodiments, R3cis Cl. In some embodiments, R3cis F. In some embodiments, R4cis halo. In some embodiments, R4cis Cl. In some embodiments, R4cis F. In some embodiments, R1c, R2c, and R5care each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of compound of Formula (III) has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is selected from any one of the compounds listed in Table III:

[0006] or a pharmaceutically acceptable salt thereof. Compounds of Formula (IV) In some embodiments, the present disclosure provides a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR1; R1is selected from H, ORNand N(RN)2; R2, R3, R4, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, NHC(=O)C1-6alkyl, C(=O)NHC1-6alkyl, and C(=O)NH2; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, and -O(CH2)n- , wherein n is 1 or 2; each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (IV): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (IV) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (IV) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is CR1. In some embodiments, if X1is N, then R2and R4are not both CH3. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, R1is H. In some embodiments, R1is ORN. In some embodiments, R1is N(RN)2. In some embodiments, R2, R3, R4, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, R5, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R5is CN. In some embodiments, R5is halo. In some embodiments, R5is C1-6alkyl. In some embodiments, R5is C1-4haloalkyl. In some embodiments, R5is C1-4haloalkyl. In some embodiments, R5is C1-6alkoxy. In some embodiments, R5is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is absent. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (IV) is selected from any one of the following formulae

[0007] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is selected from any one of the following formulae:

[0008] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is selected from any one of the compounds provided in Table IVa: Table IVa

[0009] or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides any of the compounds listed in Table IVa, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is selected from any one of the compounds of Table IVa and any one of the compound of Table IVb.

[0010] In some embodiments, the compound of Formula (IV) is selected from any one of the compounds provided in Table IVc: Table IVc

[0011] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is selected from any one of the compounds provided in Table IVd: Table IVd

[0012] In some embodiments, the compound of Formula (IV) is selected from any one of the compounds provided in the table below:

[0013] or a pharmaceutically acceptable salt thereof. Compounds of Formula (V) In some embodiments, the present disclosure provides a compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein: R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and -10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (V): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (V) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (V) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, R5, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (V) is selected from any one of the compounds provided in Table V: Table V

[0014] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V) is selected from any one of the compounds provided in Table Vb: Table Vb or a pharmaceutically acceptable salt thereof. Compounds of Formula (VI) In some embodiments, the present disclosure provides a compound of Formula (VI): or a pharmaceutically acceptable salt thereof, wherein: R2, R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3 alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (VI): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VI) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VI) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, R2, R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, R5, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R5is CN. In some embodiments, R5is halo. In some embodiments, R5is C1-6alkyl. In some embodiments, R5is C1-5haloalkyl. In some embodiments, R5is C1-5haloalkyl. In some embodiments, R5is C1-6alkoxy. In some embodiments, R5is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (VI) is selected from any one of the compounds provided in Table VI: Table VI or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (VI) is selected from any one of the compounds provided in Table VIb: Table VIb or a pharmaceutically acceptable salt thereof. Compounds of Formula (VII) In some embodiments, the present disclosure provides a compound of Formula (VII): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR3; X2is selected from N and CR4; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (VII): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VII) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VII) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is CR3. In some embodiments, X2is N. In some embodiments, X2is CR4. In some embodiments, X1is N and X2is N. In some embodiments, X1is N and X2is CR4. In some embodiments, X1is CR3and X2is CR4. In some embodiments, X1is CR3and X2is N. In some embodiments, R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (VII) is selected from any one of the compounds provided in Table VII: Table VII or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (VII) is selected from any one of the compounds provided in the table below:

[0015] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (VII) is selected from any one of the compounds provided in Table VIIb: Table VIIb or a pharmaceutically acceptable salt thereof. Compounds of Formula (VIIa) In some embodiments, the present disclosure provides a compound of Formula (VIIa): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR3; X2is selected from N and CR4; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3 alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (VIIa): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VIIa) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VIIa) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is CR3. In some embodiments, X2is N. In some embodiments, X2is CR4. In some embodiments, X1is N and X2is N. In some embodiments, X1is N and X2is CR4. In some embodiments, X1is CR3and X2is CR4. In some embodiments, X1is CR3and X2is N. In some embodiments, R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (VIIa) is selected from any one of the compounds provided in the table below: or a pharmaceutically acceptable salt thereof. Compounds of Formula (VIII) In some embodiments, the present disclosure provides a compound of Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR2; X2is selected from N and CR3; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (VIII): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VIII) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VIII) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is CR2. In some embodiments, X2is N. In some embodiments, X2is CR3. In some embodiments, X1is N and X2is N. In some embodiments, X1is N and X2is CR3. In some embodiments, X1is CR2and X2is CR3. In some embodiments, X1is CR2and X2is N. In some embodiments, R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (VIII) is selected from any one of the compounds provided in Table VIII: Table VIII or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (VIII) is selected from any one of the compounds provided in Table VIIIb: Table VIIIb or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (VIII) is selected from any one of the compounds provided in the table below: or a pharmaceutically acceptable salt thereof. Compounds of Formula (VIIIa) In some embodiments, the present disclosure provides a compound of Formula (VIIIa): (VIIIa) or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR2; X2is selected from N and CR3; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (VIIIa): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VIIIa) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (VIIIa) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, X1is N. In some embodiments, X1is CR2. In some embodiments, X2is N. In some embodiments, X2is CR3. In some embodiments, X1is N and X2is N. In some embodiments, X1is N and X2is CR3. In some embodiments, X1is CR2and X2is CR3. In some embodiments, X1is CR2and X2is N. In some embodiments, R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1 is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (VIIIa) is selected from any one of the compounds provided in the table below:

[0016] or a pharmaceutically acceptable salt thereof. Compounds of Formula (IX) In some embodiments, the present disclosure provides a compound of Formula (IX): or a pharmaceutically acceptable salt thereof, wherein: R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, NHC(=O)C1-6alkyl, C(=O)NHC1-6alkyl, and C(=O)NH2; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4- 10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, L2-Cy2, and L2-Cy2-C1-3alkylene; L2is absent or NRN, and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. In some embodiments, the compound of Formula (IX): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (IX) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (IX) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, at least one of R2, R3, R4, R5, and R6is selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, R2, R3, R4, and R6are each H. In some embodiments, R2is CN. In some embodiments, R2is halo. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-4haloalkyl. In some embodiments, R2is C1-6alkoxy. In some embodiments, R2is C1-6haloalkoxy. In some embodiments, R3is CN. In some embodiments, R3is halo. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-4haloalkyl. In some embodiments, R3is C1-6alkoxy. In some embodiments, R3is C1-6haloalkoxy. In some embodiments, R4is CN. In some embodiments, R4is halo. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-4haloalkyl. In some embodiments, R4is C1-6alkoxy. In some embodiments, R4is C1-6haloalkoxy. In some embodiments, R6is CN. In some embodiments, R6is halo. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-4haloalkyl. In some embodiments, R6is C1-6alkoxy. In some embodiments, R6is C1-6haloalkoxy. In some embodiments, L1is absent. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, L1is 4-10 membered heterocycloalkylene (e.g., piperidinyl). In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, R7is Cy1. In some embodiments, R7is Cy1-C1-3alkylene. In some embodiments, Cy1is C6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, Cy1is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, Cy2is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, Cy2is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (IX) is selected from any one of the compounds provided in Table IX: Table IX or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IX) is selected from any one of the compounds provided in Table IXb: Table IXb

[0017] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IX) is selected from any one of the compounds provided in Table IXc: Table IXc

[0018] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IX) is selected from any one of the compounds provided in the table below: or a pharmaceutically acceptable salt thereof. Compounds of Formula (X) In some embodiments, the present disclosure provides a compound of Formula (X): or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR1; each R1is independently selected from H, ORN, N(RN)2, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, -O(CH2)n- , C(=O)NRN-(CH2)n-, and NRNC(=O)-(CH2)n-, wherein n is 1 or 2; each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; ring A is selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from OH, N(R13)2NO2, CN, C2-3alkynyl optionally substituted with amido, halo, C1-6alkyl optionally substituted with C1-2- sulfonyl, C1-6alkyl optionally substituted with C1-2-sulfonylamino, C1-6alkyl optionally substituted with C1-C3-acyl, C1-4haloalkyl, C1-6alkoxy optionally substituted with C1-2- sulfonyl, C1-6alkoxy optionally substituted with C1-2-sulfonylamino, C1-6alkoxy optionally substituted with C1-C3-acyl,, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C3-10cycloalkyloxy, 4-10 membered heterocycloalkyloxy optionally substituted with C1-6alkyl, C1-2-sulfonyl, or C1-3-acyl; C3-10cycloalkylamino, 4-10 membered heterocycloalkylamino, C1-6haloalkoxy, C1-6hydroxyalkoxy, N(R13)2-C1-6alkoxy optionally substituted with R12, N(R13)2-C1-6alkyl optionally substituted with R12, , cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, , and carboxy. wherein each R12is independently selected from C1-2-sulfonyl, C1-3-acyl, C1-3- acylamido, C1-3haloacylamido, ureido, C1-2-sulfonylamino and aminocarbonyl; wherein each R13is independently selected from H and C1-6alkyl; or two R8groups taken together form =O, or two R8groups taken together with the atoms connecting them form a 5- or 6- membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring has one or more ring heteroatoms independently selected from the group consisting of O, S and N. each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; L2is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, -O(CH2)n- , and -(CH2)n-, i wherein n is 1 or 2; and ring B is selected from C6-10aryl, C3-10cycloalkyl, C3-10cycloalkenyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, the compound of Formula (X): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (X) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (IV) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (X) selectively inhibits and / or degrades AR polypeptide within the mammal. In some embodiments, the compound of Formula (X) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (X) has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, each R1is independently selected from H, ORN, N(RN)2, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, each R1is independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, In some embodiments, each R1is H. In some embodiments, L1is absent. In some embodiments, L1is C(=O)NRN. In some embodiments, L1is C(=O)NH. In some embodiments, L1is NRNC(=O). In some embodiments, L1is NHC(=O). In some embodiments, L1is C(=O). In some embodiments, L1is NRN. In some embodiments, L1is NH. In some embodiments, L1is NRNC(=O)NRN. In some embodiments, L1is NHC(=O)NH. In some embodiments, L1is CH2NRN. In some embodiments, L1is CH2NH. In some embodiments, L1is NRNCH2. In some embodiments, L1is NHCH2. In some embodiments, RNis H. In some embodiments, RNis C1-3alkyl. In some embodiments, RNis C1-3haloalkyl. In some embodiments, RNis C(=O)C1-3alkyl. In some embodiments, RNis C(=O)C6-10aryl. In some embodiments, RNis S(=O)2C1-3alkyl. In some embodiments, RNis S(=O)2C6-10aryl. In some embodiments, ring A is C6-10aryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, ring A is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, ring A is 5- 14 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R8. In some embodiments, R8is selected from halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, and Cy2-C1-3alkylene. In some embodiments, R8is halo. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-4haloalkyl. In some embodiments, R8is C1-6alkoxy. In some embodiments, R8is C1-6haloalkoxy. In some embodiments, R8is carboxy. In some embodiments, R8is Cy2. In some embodiments, R8is Cy2-C1-3alkylene. In some embodiments, one R8is , . In some e o ents, ring B is iselected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, In some embodiments, ring B is C6-10aryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, In some embodiments, ring B is 5-14 membered heteroaryl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, In some embodiments, ring B is 4-10 membered heterocycloalkyl, substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, the compound of Formula (X) is selected from any one of the following formulae or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (X) is selected from any one of the compounds provided in Table X: Table X

[0019] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (X) is selected from any one of the compounds provided in Table XI: Table XI: -0315268 COL-0315269 COL-0315270

[0020] or a pharmaceutically acceptable salt thereof. Compounds of Table A In some embodiments, the present disclosure provides any of the compounds listed in Table A. Table A

[0021] or a pharmaceutically acceptable salt thereof. In some embodiments, any of the compounds provided in Table A: (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound provided in Table A selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound provided in Table A inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound provided in Table B selectively inhibits and / or degrades AR polypeptide within the mammal. Compounds of Table B In some embodiments, the present disclosure provides any of the compounds listed in Table B. Table B or a pharmaceutically acceptable salt thereof. In some embodiments, any of the compounds provided in Table B: (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound provided in Table B selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound provided in Table B inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound provided in Table B selectively inhibits and / or degrades AR polypeptide within the mammal. Compounds of Table C In some embodiments, the present disclosure provides any of the compounds listed in Table C.

[0022] or a pharmaceutically acceptable salt thereof. In some embodiments, any of the compounds provided in Table C: (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound provided in Table C selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound provided in Table C inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound provided in Table C selectively inhibits and / or degrades AR polypeptide within the mammal. Compounds of Formula (XIII) In some embodiments, the compound of Formula (X) is a compound of Formula (XIII): or a pharmaceutically acceptable salt thereof, wherein: X1is CR1or N; X2is CR2or N; wherein X1and X2are not both N; R1and R2each independently H; halo; NH2; OH; OC1-6alkyl wherein the OC1-6alkyl is optionally substituted with a group selected from halo, amino, alkylamino, dialkylamino, acetamido, aminocarbonyl, ureido, alkylsulfonamido, acetylamido, alkylsulfonyl, and hydroxyalkyl; OC3-6cycloalkyl; O-3-6-membered heterocycloalkyl optionally substituted with a group selected from C1-C3alkyl, SO2C1-C3alkyl, and C1-C3acyl; or S-3-6 membered heterocycloalkyl optionally substituted with a group selected from C1-C3alkyl, SO2C1-C3alkyl, and C1-C3acyl; X3= CH, C(OH), or CF; R4is selected from H, CN, halo, OC1-6alkyl, C3-6cycloalkyl, CCH, CC(CH3), CC(CONH2), amido, C1-6alkyl, C1-6haloalkyl, C3-C8cycloalkyl, and C3-C8cycloalkoxy, R5is H or halo; or R4and R5together form a 5-8 membered carbocyclic or heterocyclic ring. In some embodiments of Formula (XIII), X1is CR1and X2is CR2. In some embodiments of Formula (XIII), X1is CR1and X2is N. In some embodiments of Formula (XIII), X1is N and X2is CR2. In some embodiments of Formula (XIII), R1is H and R2is not H. In some embodiments of Formula (XIII), R1is not H and R2is H. In some embodiments of Formula (XIII), R1is not H and R2is H. In some embodiments of Formula (XIII), R1is H and R2is OC1-6alkyl wherein the OC1-6alkyl is optionally substituted In some embodiments of Formula (XIII), R1is OC1-6alkyl wherein the OC1-6alkyl is optionally substituted, and R2is H. In some embodiments of Formula (XIII), X3is CH. In some embodiments of Formula (XIII), R4is H. In some embodiments of Formula (XIII), R4is CN. In some embodiments of Formula (XIII), R4is halo. In some embodiments of Formula (XIII), R4is OC1-6alkyl. In some embodiments of Formula (XIII), R4is C3-6cycloalkyl. In some embodiments of Formula (XIII), R4is CCH. In some embodiments of Formula (XIII), R4is CC(CH3). In some embodiments of Formula (XIII), R4is CC(CONH2). In some embodiments of Formula (XIII), R4is amido. In some embodiments of Formula (XIII), R4is C1-6alkyl. In some embodiments of Formula (XIII), R4is C1-6haloalkyl. In some embodiments of Formula (XIII), R4is C3-C8cycloalkyl. In some embodiments of Formula (XIII), R4is C3-C8cycloalkoxy, In some embodiments of Formula (XIII), R5is H. In some embodiments of Formula (XIII), R5is halo. In some embodiments of Formula (XIII), R4and R5together form a 5-8 membered carbocyclic or heterocyclic ring. In some embodiments, the compound of Formula (XIII): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the compound of Formula (XIII) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, the compound of Formula (XIII) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, the present disclosure provides a compound of Formula (XII): or a pharmaceutically acceptable salt thereof, wherein, in Formula (XII): p is 1, 2, 3, 4 or 5; each R1is independently selected from H, ORN, N(RN)2, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, and 5-10-membered heteroaryl ring having one or more ring heteroatoms selected from the group consisting of O, S and N, wherein the 5-10-membered heteroaryl ring isoptionally substituted with halo or wtih C1-6alkyl; m is 0, 1 or 2; W is C1-2alkylene or C2-alkenylene, wherein W is optionallly substitued with C1-3alkyl; wherein each C1-3alkyl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; Het is a 5-membered heteroaryl ring having one or more ring heteroatoms selected from the group consisting of O, S and N; o is 0, 1, 2, 3 or 4; and each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, and carboxy; or two R8groups taken together with the atoms connecting them form a 5- or 6- membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring has one or more ring heteroatoms selected from the group consisting of O, S and N. In some embodiments, the compound of Formula (XII) is selected from any one of the compounds provided in the table below:

[0023] or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (XII): (i) selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, a compound of Formula (XII) selectively inhibits and / or degrades ER polypeptide within the mammal. In some embodiments, a compound of Formula (XII) inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal. In some embodiments, a compound of Formula (XII) selectively inhibits and / or degrades AR polypeptide within the mammal. Pharmaceutically acceptable salts In some embodiments, a salt of a compound presented herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of this disclosure include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of this disclosure include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some embodiments, the compounds presented herein, or pharmaceutically acceptable salts thereof, are substantially isolated. Compositions, formulations, and routes of administration The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients. Routes of administration and dosage forms The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product. In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol, and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia. Compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant. The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols. The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No.6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000. The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners. The compounds and therapeutic agents of the present application may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Patent Nos.6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein. According to another embodiment, the present application provides an implantable drug release device impregnated with or containing a compound or a therapeutic agent, or a composition comprising a compound of the present application or a therapeutic agent, such that said compound or therapeutic agent is released from said device and is therapeutically active. Dosages and regimens In the pharmaceutical compositions of the present application, a compound of the present disclosure is present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. In some embodiments, an effective amount of the compound can range, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; or from about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, an effective amount of a compound is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg. The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month). Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein (such as cancer), which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein. Combination therapies Cancer cell growth and survival can be impacted by multiple biochemical pathways. Thus, it is useful to combine different chemotherapeutic agents to treat cancer. Targeting more than one biochemical pathways may reduce the likelihood of drug- resistance arising in a cell population, and / or reduce the toxicity of treatment. The AR and / or ER inhibitors and / or degraders of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation, or surgery. The compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat and zoledronate. Definitions As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value). At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl. At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3- yl, or pyridin-4-yl ring. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like. As used herein, the term “Cn-malkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n- hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, “Cn-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “Cn-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-1,2-diyl, propan- 1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms. As used herein, the term “Cn-malkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-mhaloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “amino” refers to a group of formula –NH2. As used herein, the term “Cn-malkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n- butyl)amino and N-(tert-butyl)amino), and the like. As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “cyano-C1-3alkyl” refers to a group of formula -(C1-3alkylene)-CN. As used herein, the term “HO-C1-3alkyl” refers to a group of formula -(C1-3alkylene)-OH. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term “Cn-malkoxycarbonyl” refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like. As used herein, the term “Cn-malkylcarbonyl” refers to a group of formula -C(O)- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n- propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert- butylcarbonyl), and the like. As used herein, the term “Cn-malkylcarbonylamino” refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonylamino” refers to a group of formula -NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonyl” refers to a group of formula -S(O)2NH2. As used herein, the term “Cn-malkylaminosulfonyl” refers to a group of formula -S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminosulfonyl” refers to a group of formula -S(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonylamino” refers to a group of formula - NHS(O)2NH2. As used herein, the term “Cn-malkylaminosulfonylamino” refers to a group of formula -NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminosulfonylamino” refers to a group of formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2. As used herein, the term “Cn-malkylaminocarbonylamino” refers to a group of formula -NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminocarbonylamino” refers to a group of formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “carbamyl” to a group of formula –C(O)NH2. As used herein, the term “Cn-malkylcarbamyl” refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-m-alkyl)carbamyl” refers to a group of formula – C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “thio” refers to a group of formula -SH. As used herein, the term “Cn-malkylthio” refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfinyl” refers to a group of formula -S(O)- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonyl” refers to a group of formula -S(O)2- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O). As used herein, the term “carboxy” refers to a -C(O)OH group. As used herein, the term “cyano-C1-3alkyl” refers to a group of formula -(C1-3alkylene)-CN. As used herein, the term “HO-C1-3alkyl” refers to a group of formula -(C1-3alkylene)-OH. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings). The term "Cn-m aryl" refers to an aryl group havingfrom n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl. As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin- 2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3-position. As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)- configuration. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the AR and / or the ER protein with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the AR and / or the ER protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the AR or the ER protein. As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology). As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring. SYNTHETIC EXAMPLES Synthesis of UP-001 Scheme 1. Synthetic route of UP-001 Compound 2 : To a solution of 6-fluoro-1H-indole (60 g, 0.44 mol) in DCM (200 mL) was added DMAP (5.42 g, 0.04 mol), (Boc)2O (193.81 g, 0.88 mol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 2 hours. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 10%) to give tert-butyl (6-fluoroindol-1-yl) formate (70 g, 66.73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 9.6 Hz, 1H), 7.56 (d, J = 3.6 Hz, 1H), 7.46 (dd, J = 8.6, 5.4 Hz, 1H), 6.98 (td, J = 9.0, 2.4 Hz, 1H), 6.53 (d, J = 3.7 Hz, 1H), 1.67 (s, 9H).

[0024] Compound 4: To a solution of tert-butyl (6-fluoroindol-1-yl) formate (30 g, 127 mmol) in dry THF (300 mL) was added LDA (2 M in THF, 127 mL, 254 mmol) dropwise at -78 °C under an atmosphere of N2. After addition, the solution was stirred at - 78 °C for 30 minutes. Then trimethoxyborane (19.80 g, 190.5 mmol) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The final mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 100%) to give tert-butyl [2-(dihydroxyboranyl)-6-fluoroindol-1- yl] formate (26.5 g, 74.49% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.22 (s, 2H), 7.81 (dd, J = 10.6, 2.3 Hz, 1H), 7.58 (dd, J = 8.6, 5.6 Hz, 1H), 7.08 (td, J = 9.1, 2.4 Hz, 1H), 6.64 (s, 1H), 1.60 (s, 9H). Compound 6: To a solution of 2-chloro-1,8-naphthyridine (10 g, 60.8 mmol) in Dioxane / H2O=4:1 (300 mL) was added tert-butyl [2-(dihydroxyboranyl)-6-fluoroindol-1- yl] formate (18.73 g, 66.8 mmol), Pd(dppf)Cl2(6.67 g, 9.12 mmol) and K2CO3(25.21 g, 182.4 mmol) slowly at 20 °C under N2. The mixture was heated at 100 °C for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with DCM / MeOH, 0% to 10%) to give tert-butyl [6-fluoro-2-(1,8-naphthyridin-2-yl)indol-1- yl] formate (14.1 g, 63.65% yield) as a yellow solid. LCMS: tR= 1.459 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 364.15 [M+H]+ Compound UP-001 : A solution / mixture of tert-butyl [6-fluoro-2-(1,8- naphthyridin-2-yl)indol-1-yl] formate (13 g, 0.0357 mol) in HCl dioxane solution (4M, 150 mL) was stirred at room temperature for 8 hours. The mixture was concentrated under reduced pressure. The residue was triturated in PE / EtOAc, filtered, and dried under vacuum to provide 2-(6-fluoro-1H-indol-2-yl)-1,8-naphthyridine hydrochloride (10.36 g, 96.92% yield) as a yellow solid. LCMS: tR= 1.243 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 264.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 9.16 (dd, J = 4.6, 1.8 Hz, 1H), 8.70 (d, J = 7.9 Hz, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 8.0, 4.7 Hz, 1H), 7.70 (dd, J = 8.7, 5.5 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.31 (dd, J = 10.0, 2.2 Hz, 1H), 7.00 – 6.90 (m, 1H). Synthesis of UP-002

[0025] Scheme 1. Synthetic route of UP-002 Compound 2: To a solution of 2,7-dichloro-1,8-naphthyridine (500 mg, 2.51 mmol) in MeOH (10 mL) was added Sodium Methylate (135.71 mg, 2.51 mmol) under an atmosphere ofN2, the solution was stirred at 25 for 16 hours. Then the resulting mixture was dilutedwith water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 2% to 3%) to give 2-chloro-7-methoxy-1,8-naphthyridine (560 mg, 91.63% yield) as a white solid. LCMS: tR= 1.448 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 194.95 [M+H]+ Compound 3: To a solution of 2-chloro-7-methoxy-1,8-naphthyridine (100 mg, 0.51 mmol) in dioxane / H2O=5 / 1 (1 mL) was added tert-butyl [2-(dihydroxyboranyl)-6-fluoroindol-1-yl] formate (215.86 mg, 0.77 mmol), K2CO3(213.04 mg, 1.54 mmol), Pd(dppf)Cl2.DCM (41.65 mg, 0.05 mmol) at 25 under N2. The mixture was reacted at 100 for 2 hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 20% to 30%) to give tert-butyl [6-fluoro-2-(7- methoxy-1,8-naphthyridin-2-yl)indol-1-yl] formate (70 mg, 34.55% yield) as a white solid. LCMS: tR= 2.124 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 394.10 [M+H]+ UP-002: To a solution of tert-butyl [6-fluoro-2-(7-methoxy-1,8-naphthyridin-2-yl)indol-1- yl] formate (60 mg, 0.15 mmol) in HCL in EtOAc (4M) (2 mL) under an atmosphere of N2, the solution was stirred at 25 for 16 hours. Then the reaction mixture was concentrated in vacuo, the residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to give the 2-(6-fluoro-1H-indol-2-yl)-7-methoxy-1,8-naphthyridine (26 mg, 58.25% yield) as a yellow solid. % yield) as a white solid. LCMS: tR= 1.418 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 294.05 [M+H]+1H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.63 (dd, J = 8.7, 5.5 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 10.1, 2.3 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.97 – 6.86 (m, 1H), 4.04 (s, 3H). Synthesis of UP-003 Compound 3: To a solution of 2,6-dichloro-1,8-naphthyridine (550 mg, 2.7633 mmol) in 1,4-dioxane / H2O=8:1 (18 mL) was added (1-(tert-butoxycarbonyl)-6-fluoro- 1H-indol-2-yl)boronic acid (774 mg, 2.7633 mmol), CsF (1259 mg, 8.2899 mmol) and Pd-118 (180 mg, 0.27633 mmol). Then the reaction mixture was stirred at 50 for 3 h under N2. After that, the mixture was diluted with ethyl acetate (25 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered and concentrated to get crude which was purified by flash chromatography (PE / EtOAc = 1 / 2,V / V) to afford tert-butyl 2-(6-chloro-1,8-naphthyridin-2-yl)-6-fluoro-1H-indole-1- carboxylate (530 mg, yield: 45.68%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 10.4, 2.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.4, 5.6 Hz, 1H), 7.07 – 7.02 (m, 2H), 1.33 (s, 9H). Compound UP-003: To a solution of tert-butyl 2-(6-chloro-1,8-naphthyridin-2- yl)-6-fluoro-1H-indole-1-carboxylate (80 mg, 0.2006 mmol) in 1,4-dioxane (2 mL) was added 4 M HCl in dioxane (2 ml) at 0 . The obtained mixture was stirred at 25 for 2 hours. After the reaction was done shown by LCMS, the solvent was removed, filtered and concentrated to afford 6-chloro-2-(6-fluoro-1H-indol-2-yl)-1,8-naphthyridine (26.60 mg, 44.37% yield) as a white solid. LCMS: tR= 0.899 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 298.00 [M+H]+1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 9.16 (d, J = 2.8 Hz, 1H), 8.77 (d, J = 2.8 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.28 (dd, J = 8.8, 1.2 Hz, 1H), 7.77 (dd, J = 8.4, 4.8 Hz, 1H), 7.53 – 7.51 (m, 1H), 7.11 (dd, J = 12.8, 8.4 Hz, 1H), 6.60 (dd, J = 3.2, 2.4 Hz, 1H). Synthesis of UP-004

[0026] Compound 2: To a solution of tert-butyl [2-(6-chloro-1,8-naphthyridin-2-yl)-6-fluoroindol-1-yl] formate (130 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added MeOH (52.21 mg, 1.63 mmol), Cs2CO3(265.46 mg, 0.81 mmol), tBuBrettPhos-Pd-G3 (30.94 mg, 0.03 mmol) and tBuBrettPhos (15.80 mg, 0.03 mmol). Then the reaction mixture was stirred at 50 for 2 h under N2. After that, Then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with water and brine, and dried over Na2SO4, filtered and concentrated to get crude which was purified by flash chromatography(PE / EtOAc=3 / 1,V / V) to afford tert-butyl [6-fluoro-2-(6- methoxy-1,8-naphthyridin-2-yl)indol-1-yl] formate (100 mg, yield: 70.02%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.23 (s, 1H), 7.20 (m, 1H), 7.15 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 1.20 (s, 9H). UP-004: To a solution of tert-butyl [6-fluoro-2-(6-methoxy-1,8-naphthyridin-2-yl)indol-1- yl] formate (100 mg, 0.25 mmol) in HCL in EtOAc (4M) (2 mL) under an atmosphere of N2, the solution was stirred at 25 for 16 hours. Then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 40% to 50%) to give 2-(6-fluoro-1H-indol-2-yl)-6-methoxy-1,8-naphthyridine (25 mg, 33.61% yield) as a yellow solid. LCMS: tR= 1.687 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 294.00 [M+H]+1H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 8.82 (d, J = 3.1 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 3.1 Hz, 1H), 7.63 (dd, J = 8.6, 5.5 Hz, 1H), 7.39 (s, 1H), 7.25 (d, J = 9.9 Hz, 1H), 6.90 (t, J = 9.3 Hz, 1H), 3.97 (s, 3H). Synthesis of UP-005 Compound 3: To a solution of compound 1 (550 mg, 2.76 mmol) in 1,4- dioxane / H2O=8:1 (18 mL) was added compound 2 (774 mg, 2.76 mmol), CsF (1259 mg, 8.28 mmol) and Pd(dppf)Cl2(180 mg, 0.276 mmol). Then the reaction mixture was stirred at 50 for 3 hours under N2. After that, the mixture was diluted with ethyl acetate (25 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered, and concentrated to get crude which was purified by flash chromatography (PE / EtOAc=1 / 2) to afford compound 3 (530 mg, yield: 45.6%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 9.06d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 10.4, 2.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.4, 5.6 Hz, 1H), 7.07 – 7.02 (m, 2H), 1.33 (s, 9H). Compound 3: To a solution of compound 3 (230 mg, 0.576 mmol) in toluene / H2O=10:1 (11 mL) was added CH3BF3K (77 mg, 0.634 mmol), Sphos-Pd-G3 (50 mg, 0.0576 mmol), and K3PO4(367 mg, 1.73 mmol). Then the reaction mixture was stirred at 80 for 16 hours under N2. After that, the mixture was diluted with ethyl acetate (25 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered and concentrated to get crude which was purified by flash chromatography (DCM / MeOH=10 / 1) to afford compound 4 (25 mg, yield: 10.3%) as orange solid. 1H NMR (400MHz, CDCl3) δ 9.00 (d,J = 2.4Hz, 1H), 8.13 (d,J = 8.4Hz, 1H), 7.97 – 7.93 (m, 2H), 7.66 (d,J = 8.4Hz, 1H), 7.54 (dd,J = 8.4, 5.6Hz, 1H), 7.06 – 6.99 (m, 2H), 2.58 (s, 3H), 1.29 (s, 9H). Compound UP-005 ENBJ231036-001 : To a solution of compound 4 (20 mg, 0.0529 mmol) in HCl in EtOAc (2 mL), the mixture was stirred at 25 for 2 hours. LCMS (ENBJ231036-001-P1M4) showed starting material was consumed and ~80% of desired product was detected. The mixture was diluted with petroleum ether and the mixture was filtered and collected the filter cake to give UP-005 (13.63 mg, 86.39% yield) as yellow solid. LCMS: tR= 1.316 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 278 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.8, 5.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 10.0, 2.0Hz, 1H), 6.99 – 6.88 (m, 1H), 2.59 – 2.53 (m, 3H). Synthesis of UP-006 1 UP-006 Compound UP-006: To a solution of 2-chloro-7-methoxy-1,8-naphthyridine (100 mg, 0.51 mmol) in 1,4 Dioxane (5 mL) was added 4-fluorobenzamide (71.48 mg, 0.51 mmol) Cs2CO3(502.22 mg, 1.54 mmol), Xantphos (44.55 mg, 0.08 mmol) and PD2(DBA)3(70.57 mg, 0.08 mmol) at 25 under N2. The mixture was reacted at 100 for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 3% to 4%) to give 4-fluoro-N-(7-methoxy-1,8-naphthyridin-2- yl)benzamide (20 mg, 13.10% yield) as a white solid. LCMS: tR= 1.610 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 298.00 [M+H]+1H NMR (400.33 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.37 (m, 2H), 8.27 (d, J = 8.7 Hz, 1H), 8.19 (m, 2H), 7.36 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H). Synthesis of UP-007 Compound UP-007: To a solution of 2,6-dichloro-1,8-naphthyridine (1.5 g, 7.5 mmol) in 1,4-dioxane (10 mL) was added 4-fluorobenzamide (152 mg, 0.50412 mmol), Cs2CO3(6.1 g, 18.75 mmol), PD2(DBA) (3690 mg, 0.75 mmol) and Xantphos (430 mg, 0.75 mmol). Then the reaction mixture was stirred at 100 for 16 h under N2. After that, the mixture was diluted with ethyl acetate (25 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered and concentrated to get crude which was purified by flash chromatography (PE / EtOAc = 3 / 1, V / V) to afford N- (6-chloro-1,8-naphthyridin-2-yl)-4-fluorobenzamide (770 mg, yield: 33.33%) as a yellow solid. LCMS: tR= 0.899 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 302.00 [M+H]+1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 9.01 (d, J = 2.8 Hz, 1H), 8.63 (d, J = 2.8 Hz, 1H), 8.50 (q, J = 9.2 Hz, 2H), 8.23 – 8.14 (m, 2H), 7.38 (t, J = 8.8 Hz, 2H). Synthesis of UP-008

[0027] Compound UP-025: To a solution of N-(6-chloro-1,8-naphthyridin-2-yl)-4- fluorobenzamide (250 mg, 0.83 mmol) in 1,4-dioxane (5 mL) was added MeOH (133 mg, 4.14 mmol), Cs2CO3(675 mg, 2.07 mmol), tBuBrettPhos Pd G3 (79 mg, 0.08 mmol) and t-butylBrettPhos (40 mg, 0.08 mmol). Then the reaction mixture was stirred at 50 for 3 h under N2. After that, the mixture was diluted with ethyl acetate (25 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered and concentrated to get crude which was purified by flash chromatography(PE / EtOAc=3 / 1,V / V) to afford 4-fluoro-N-(6-methoxy-1,8-naphthyridin- 2-yl)benzamide (23.50 mg, yield: 9.54%) as a yellow solid. LCMS: tR= 1.144 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 298.00 [M+H]+1H NMR (400.35 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.78 (d, J = 3.2 Hz, 1H), 8.42 (d, J = 1.4 Hz, 2H), 8.18 (m, 2H), 7.86 (d, J = 3.2 Hz, 1H), 7.36 (m, 2H), 3.95 (s, 3H). Synthesis of UP-009

[0028] UP-009: To a solution of N-(6-chloro-1,8-naphthyridin-2-yl)-4-fluorobenzamide (120 mg, 0.40 mmol) in DMF / H2O = 4:1 (5 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (124.81 mg, 1.00 mmol), CsF (181.25 mg, 1.19 mmol) and Pd(dtbpf)Cl2(25.68 mg, 0.04 mmol) under an atmosphere of N2, the solution was stirred at 100 for 2 hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 70% to 80%) to give 4-fluoro-N-(6- methyl-1,8-naphthyridin-2-yl)benzamide (12 mg, 10.74% yield) as a red solid. LCMS: tR= 1.079 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 281.95 [M+H]+1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.49 – 8.35 (m, 2H), 8.18 (m, 3H), 7.37 (t, J = 8.8 Hz, 2H), 3.31 (s, 3H). Synthesis of UP-010 Compound UP-010: To a solution of compound 1 (100 mg, 0.478 mmol) in 1,4- dioxane (5 mL) was added compound 2 (318 mg, 2.39 mmol), PD2(DBA) (344 mg, 0.0478 mmol), t-butylBrettPhos (23 mg, 0.0478 mmol) and K3PO4(305 mg, 1.43 mmol). Then the reaction mixture was stirred at 80 for 16 hours under N2. After that, the mixture was diluted with ethyl acetate (25 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered, and concentrated to get crude which was purified by flash chromatography (DCM / MeOH=10 / 1) to afford UP-010 (65.78 mg, yield: 52.6%) as yellow solid. LCMS: tR= 1.373 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 262 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.86 (s, 1H), 8.28 (s, 2H), 7.52 (s, 2H), 7.48 – 7.40 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 6.0, 3.2 Hz, 2H) Synthesis of UP-011 Compound UP-011: To a solution of 1,3-benzothiazol-2-amine (100 mg, 0.67 mmol) in Dioxane (10 mL) was added 2-bromo-1,8-naphthyridine (153.10 mg, 0.73 mmol), Pd2(dba)3(91.45 mg, 0.10 mmol), Xantphos (57.79 mg, 0.10 mmol) and Cs2CO3(650.79 mg, 2.00 mmol) slowly at 20 °C under N2. The mixture was heated at 100 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford N-(1,3-benzothiazol-2-yl)-1,8-naphthyridin-2-amine (46 mg, 24.83% yield) as a yellow solid. LCMS: tR= 0.899 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 279.15 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.94 (s, 1H), 8.42 – 8.27 (m, 2H), 8.01 (d, J = 7.4 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.52 – 7.33 (m, 3H), 7.31 – 7.22 (m, 1H). Synthesis of UP-012 Compound UP-012 ENBJ230989-001 : A solution of 1,3-benzoxazol-2-amine (100 mg, 0.75 mmol) in dioxane (3 mL) was add 2-bromo-1,8-naphthyridine (155.84 mg, 0.75 mmol), Cs2CO3(728.70 mg, 2.24 mmol) and xantphos (43.09 mg, 0.07 mmol), Pd2(dba)3(68.27 mg, 0.07 mmol) was stirred under nitrogen at 100 for 16 H. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, the residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% NH4OH) to give the N-(1,3-benzoxazol-2-yl)-1,8-naphthyridin-2-amine (25 mg, 12.78% yield) as a white solid. LCMS: tR= 1.190 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 263.15 [M+H]+1H NMR (400.33 MHz, DMSO-d6) δ 9.10 (d, J = 5.2 Hz, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.66 (d, J = 9.1 Hz, 1H), 8.19 (s, 1H), 7.86 (m, 1H), 7.66 (m, 2H), 7.34 (m, 2H). Synthesis of UP-014

[0029] Compound 3: To a solution of compound 2 (650 mg, 2.52 mmol) in THF (6 mL) was added n-BuLi (1.2 mL, 3.03 mmol) at -65°C, the mixture was stirred at -65°C for 0.25 h. Then, compound 1 (400 mg, 2.52 mmol) in THF (2 mL) was added in the mixture at -65°C, the mixture was stirred at -65°C for 1 hour. The mixture was diluted with saturated aq. NH4Cl (20 mL) and extracted with ethyl acetate (20 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / petroleum ether= 0- 80%) to give compound 3 (350 mg, 30.1% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (dd, J = 4.0, 2.0 Hz, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.64 (dd, J = 8.0, 2.0 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.95 (dd, J =11.6, 4.4 Hz, 3H), 7.79 (dd, J = 8.0, 4.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.60 – 7.48 (m, 4H), 7.38 (dd, J = 11.2, 4.0 Hz, 1H).

[0030] Compound UP-014: To a solution of compound 3 (80 mg) in MeOH (5 mL) was added 2M KOH (5 mL), the mixture was stirred at 85°C for 12 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: ACN--H2O (0.1%FA), Gradient: 60-70%) to give UP-014 (22.35 mg, 41.8% yield) as yellow solid. LCMS: tR= 1.251 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 274.20 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.79 (s, 1H), 8.19 – 8.05 (m, 4H), 7.35 (dd, J = 12.4, 5.6 Hz, 2H). Synthesis of UP-018 Compound 3: To a mixture of compound 1 (2 g, 0.0115 mol), DIPEA (22.9 g, 0.023 mol) and compound 2 (2.72 g, 0.0115mol) in DMF (30 mL) was added HATU (5.25 g, 0.0138mol) at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0- 60%) to give compound 3 (1.6 g, 32.1% yield) as yellow solid. LCMS: tR= 1.418 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 394.00 [M+H]+ Compound UP-014: To a mixture of compound 3 (300 mg, 0.763 mmol), Cs2CO3(372 mg, 1.14 mmol) and 1,10-Phenanthroline (13.7mg, 0.0763 mmol) in DMSO (6 mL) was added CuI (7.27 mg, 0.0381 mmol), the mixture was stirred at 100°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-70%) and purified / separated by prep-HPLC (Column: Gemini-C18, Mobile phase: ACN---H2O (0.1%TFA), Gradient: 30-65%) to give UP- 018(3.12 mg, 1.52% yield) as yellow solid. LCMS: tR= 0.938 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 266.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.25 (dd, J = 4.0, 2.0 Hz, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.63 (dd, J = 8.0, 2.0 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 9.2, 4.4 Hz, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.78 (dd, J = 8.0, 4.4 Hz, 1H), 7.45 (td, J = 9.2, 2.8 Hz, 1H). Synthesis of UP-020

[0031] Compound UP-020: To a solution of 6-fluoro-2,3-dihydroisoindol-1-one (100 mg, 0.6616 mmol) in 1,4-dioxane (5 mL) was added 2-bromo-1,8-naphthyridine (138 mg, 0.6616 mmol), Cs2CO3(539 mg, 1.654 mmol), Pd2(dba)3(61 mg, 0.06616 mmol) and Xantphos (38 mg, 0.06616 mmol). Then the reaction mixture was stirred at 100 for 16 h under N2. After that, the mixture was diluted with water (10 ml) and ethyl acetate (10 mL) for 3 times. The organic phase was washed with water and brine, and dried over Na2SO4, filtered and concentrated to get crude which was purified by flash chromatography (PE / EtOAc = 2 / 1, V / V) to afford 6-fluoro-2-(1,8-naphthyridin-2-yl)- 3H-isoindol-1-one (23.8 mg, yield: 12.56%) as a orange solid. LCMS: tR= 0.899 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 280.05 [M+H]+1H NMR (400 MHz, MeOD) δ 9.00 – 8.95 (m, 4H), 8.47 – 8.41 (m, 4H), 7.75 (dd, J = 8.4, 4.4 Hz, 2H), 7.62 – 7.56 (m, 4H), 7.52 – 7.47 (m, 2H), 5.32 (s, 4H). Synthesis of UP-021 HN Compound UP-021: To a solution of 6-fluoro-2,3-dihydroisoindol-1-one (100 mg, 0.66 mmol) in Dioxane (10 mL) was added 2-bromo-1,8-naphthyridine (138.30 mg, 0.66 mmol), Pd2(dba)3(90.88 mg, 0.10 mmol), Xantphos (57.42 mg, 0.10 mmol), and Cs2CO3(646.69 mg, 1.98 mmol) slowly at 20 °C under N2. The mixture was heated at 100 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 6-fluoro-2-(1,8-naphthyridin-2-yl)-3H-isoindol-1-one (26.43 mg, 14.30% yield) as a yellow solid. LCMS: tR= 1.072 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 280.15 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.02(dd, J = 4.2, 1.9 Hz, 1H), 8.85 (d, J = 8.9 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.44 (dd, J = 8.0, 1.8 Hz, 1H), 7.93 (dd, J = 8.4, 5.2 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.0, 4.3 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 5.28 (s, 2H). Synthesis of UP-023

[0032] Compound 3: To a solution of 1,8-naphthyridin-2-amine1 (1.1 g, 7.6 mmol) in DMF (20 mL) was added 2-nitrobenzoic acid (1.27 g, 7.6 mmol), HATU (3.47 g, 9.1 mmol) and DIPEA (2.95 g, 22.8 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 8 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give N-(1,8-naphthyridin-2-yl)- 2-nitrobenzamide (2.1 g, 93.42% yield) as a white solid. LCMS: tR= 0.953 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 294.90 [M+H]+ Compound 4: To a solution of N-(1,8-naphthyridin-2-yl)-2-nitrobenzamide (2.1 g, 7.1 mmol) in EtOH / H2O=1:2 (120 mL) was added NH4Cl (1.52 g, 28.4 mmol), Fe (1.98 g, 35.5 mmol) slowly at 20 °C under N2. The mixture was heated at 50 °C for 2 hours. The resulting mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with DCM / MeOH, 0% to 15%) to give 2-amino-N-(1,8-naphthyridin-2-yl)benzamide (0.406 g, 21.13% yield) as a yellow solid. LCMS: tR= 0.919 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 265.00 [M+H]+

[0033] Compound UP-023: To a solution of 2-amino-N-(1,8-naphthyridin-2- yl)benzamide (400 mg, 1.51 mmol) in ACN (20 mL) was added AcOH (181.77 mg, 3.02 mmol), tert-Butyl nitrite (234.11 mg, 2.27 mmol) slowly at 20 °C under N2. The mixture was heated at 50 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was triturated in EtOAc, filtered, and dried under vacuum to provide 7-(1,8-naphthyridin-2-yl)-7-azabicyclo[4.2.0]octa-1(6),2,4-trien-8-one (201 mg, 53.71% yield) as a yellow solid. LCMS: tR= 0.956 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 248.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.22 (dd, J = 4.2, 2.0 Hz, 1H), 8.82 (d, J = 8.5 Hz, 1H), 8.68 (dd, J = 8.2, 2.0 Hz, 1H), 8.39 (t, J = 8.1 Hz, 2H), 8.26 – 8.15 (m, 1H), 8.06 (dt, J = 7.4, 1.5 Hz, 2H), 7.82 (dd, J = 8.2, 4.2 Hz, 1H). Synthesis of UP-024 Scheme 1. Synthetic route of UP-024

[0034] UP-024: To a solution of 3,4-dihydro-2H-isoquinolin-1-one (100 mg, 0.68 mmol) in 1,4 Dioxane (3 mL) was added 2-bromo-1,8-naphthyridine (142.04 mg, 0.68 mmol) Cs2CO3(664.15 mg, 2.04 mmol), xantphos (58.97 mg, 0.10 mmol) and PD2(DBA)3(93.33 mg, 0.10 mmol) at 25 under N2. The mixture was reacted at 100 for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 30% to 40%) to give 2-(1,8-naphthyridin-2-yl)-3,4-dihydroisoquinolin-1-one (26 mg, 13.63% yield) as a faint yellow solid . LCMS: tR= 1.050 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 276.15 [M+H]+1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.48 – 8.38 (m, 2H), 8.20 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.60 (m, 2H), 7.44 (m, 2H), 4.41 (t, J = 5.8 Hz, 2H), 3.18 (t, J = 5.5 Hz, 2H). Synthesis of UP-025 Compound UP-025: To a solution of 5,6-difluoro-2,3-dihydroisoindol-1-one (100 mg, 0.59 mmol) in 1,4-dioxane (3 mL) was added 2-bromo-1,8-naphthyridine (98.89 mg, 0.47 mmol), Cs2CO3(577.97 mg, 1.77 mmol), Xantphos (51.27 mg, 0.09 mmol) and PD2(DBA)3(81.22 mg, 0.09 mmol) under an atmosphere of N2, the solution was stirred at 100 for 16 hours. Then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 70% to 80%) to give 5,6-difluoro-2-(1,8-naphthyridin-2-yl)-3H-isoindol-1-one (10 mg, 5.63% yield) as a yellow solid. LCMS: tR= 1.126 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 298.00 [M+H]+1H NMR (400.35 MHz, DMSO-d6) δ 9.10 – 8.95 (m, 1H), 8.88 – 8.76 (m, 1H), 8.61 – 8.51 (m, 1H), 8.49 – 8.40 (m, 1H), 8.02 – 7.84 (m, 2H), 7.63 – 7.50 (m, 1H), 5.26 (s, 2H). Synthesis of UP-026 Compound UP-026: To a solution of 4-fluoro-2,3-dihydroisoindol-1-one (100 mg, 0.66 mmol) in Dioxane (10 mL) was added 2-bromo-1,8-naphthyridine (138.30 mg, 0.66 mmol), Pd2(dba)3(90.88 mg, 0.10 mmol), Xantphos (57.42 mg, 0.10 mmol), and Potassium carbonate (274.32 mg, 1.98 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 4-fluoro-2-(1,8-naphthyridin-2-yl)-3H- isoindol-1-one (100.53 mg, 54.41% yield) as a yellow solid. LCMS: tR= 1.053 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 280.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.04 (dd, J = 4.2, 1.9 Hz, 1H), 8.84 (d, J = 8.9 Hz, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.45 (dd, J = 8.0, 1.9 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.69 – 7.55 (m, 3H), 5.35 (s, 2H). Synthesis of UP-027 Compound UP-027: To a solution of 7-fluoro-2,3-dihydroisoindol-1-one (100 mg, 0.6616 mmol) in Dioxane (10 mL) was added 2-bromo-1,8-naphthyridine (138.30 mg, 0.6616 mmol), Pd2(dba)3(90.88 mg, 0.0992 mmol), Xantphos (57.42 mg, 0.0992 mmol), and Potassium carbonate (274.32 mg, 1.9848 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 4 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 7-fluoro-2-(1,8- naphthyridin-2-yl)-3H-isoindol-1-one (27.6 mg, 14.93% yield) as a yellow solid. LCMS: tR= 1.017 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 279.95 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.8 Hz, 1H), 8.81 (d, J = 8.9 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.44 (dd, J = 8.0, 1.8 Hz, 1H), 7.78 (td, J = 7.9, 4.9 Hz, 1H), 7.62 – 7.54 (m, 2H), 7.38 – 7.32 (m, 1H), 5.29 (s, 2H). Synthesis of UP-028

[0035] Scheme 1. Synthetic route of UP-028 Compound 3: To a solution of 4-aminopyrimidine-5-carbaldehyde (1 g, 8.12 mmol) in MeCN (10 mL) was add (cyanomethyl)triphenylphosphanium chloride (2.74 g, 8.12 mmol) and TEA (1.64 g, 16.25 mmol) under an atmosphere of N2, the solution was stirred at 80 for 1 hours. Then the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 40% to 50%) to give pyrido[2,3- d]pyrimidin-7-amine (180 mg, 67.41% yield) as a white solid. LCMS: tR= 0.708 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 147.05 [M+H]+ UP-028: To a solution of pyrido[2,3-d]pyrimidin-7-amine (700 mg, 4.79 mmol) in DCM (2 mL) Was add triethylamine (1453.98 mg, 14.37 mmol) under an atmosphere of N2, the solution was stirred at 0 for 1 hours. Then 4-fluorobenzoyl chloride (759.42 mg, 4.79 mmol) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 15 hours. Then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 40% to 50%) to give 4-fluoro-N-{pyrido[2,3-d]pyrimidin-7-yl}benzamide (9.0 mg, 0.70% yield) as a yellow solid. LCMS: tR= 0.989 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 269.00 [M+H]+1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.77 (m, 2H), 8.06 (m, 2H), 7.46 (d, J = 16.4 Hz, 1H), 7.31 (t, J = 8.6 Hz, 2H), 6.77 (d, J = 16.5 Hz, 1H). Synthesis of UP-031 Compound 2: To a solution of compound 1 (100 mg, 0.505 mmol) in DMF (2 mL) was added NaH (40.4 mg, 1.01 mmol) at 0°C, the mixture was stirred at 0°C for 0.5 hour. Then, SEMCl (168 mg, 1.01 mmol) was added in the mixture at 0°C, the mixture was stirred at 0°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-18%) to give compound 2(50 mg, 27.0% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 5.62 (s, 2H), 3.65 – 3.53 (m, 2H), 0.89 – 0.82 (m,2H), -0.06 – -0.15 (m, 9H). Compound UP-014: To a mixture of compound 2 (40 mg, 0.121 mmol), compound 3 (16.9 mg, 0.121 mmol), Xantphos (4.22 mg, 0.007 mmol) and Cs2CO3(118 mg, 0.364 mmol) in dioxane (2 mL) was added Pd2(dba)3(3.89 mg, 0.004 mmol) under N2, the mixture was stirred at 100°C for 16 hours. The mixture was diluted with saturated aq. NH4Cl (10.0 mL) and extracted with dichloromethane (10 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0- 6%) to give compound 4 (50 mg, 95.5% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.53 (s, 1H), 8.18 – 8.04 (m, 4H), 7.35 (t, J = 8.8 Hz, 2H), 5.62 (s, 2H), 3.58 (dd, J = 12.8, 4.4 Hz, 2H), 0.87 –0.81 (m, 2H), -0.05 – -0.11 (m, 9H).

[0036] Compound UP-031: To a solution of 4 compound 4 (40 mg, 0.103 mmol) in DCM (0.6 mL) was added TFA (0.2 mL) at 0°C, the mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to remove the solvent. Then the crude product was purified by prep-HPLC (Column: Gemini-C18150 x 21.2 mm, Mobile phase: ACN---H2O (0.1%TFA), Gradient: 10-45%) to give UP-031(21.27 mg, 80.3% yield) as white solid. LCMS: tR= 0.759 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 257.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.79 (s, 1H), 8.19 – 8.05 (m, 4H), 7.35 (dd, J = 12.4, 5.6 Hz, 2H). Synthesis of UP-032

[0037] Compound 3: To a solution of 5-fluoro-3-iodopyridin-2-amine (1.5 g, 6.30 mmol) in Dioxane / H2O=4:1 (20 mL) was added ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (1.42 g, 6.30 mmol), Pd(dppf)Cl2 / DCM (772.03 mg, 0.95 mmol) and K2CO3(2.61 g, 18.91 mmol) slowly at 20 °C under N2. The mixture was heated at 50 °C for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 100%) to give ethyl (2E)-3-(2-amino-5- fluoropyridin-3-yl)prop-2-enoate (830 mg, 62.65% yield) as a yellow solid. LCMS: tR= 1.033 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 211.00 [M+H]+ Compound 4: To a solution of ethyl (2E)-3-(2-amino-5-fluoropyridin-3-yl)prop- 2-enoate (830 mg, 3.95 mmol) in MeOH (20 mL) was added Sodium methanolate (725.21 mg, 13.42 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 8 hours. The mixture was concentrated under reduced pressure. The residue was triturated in EtOAc, filtered, and dried under vacuum to provide 6-fluoro-1H-1,8-naphthyridin-2- one (530 mg, 81.78% yield) as a brown solid. LCMS: tR= 0.884 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 165.00 [M+H]+ Compound 5: To a solution of 6-fluoro-1H-1,8-naphthyridin-2-one (530 mg, 3.23 mmol) in POCl3(7.43 g, 48.44 mmol) at 20 °C under N2. The mixture was heated at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was triturated in EtOAc, filtered, and dried under vacuum to provide 2-chloro-6- fluoro-1,8-naphthyridine (230 mg, 39.01% yield) as a brown solid. LCMS: tR= 0.926 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 182.95 [M+H]+ Compound UP-032: To a solution of 2-chloro-6-fluoro-1,8-naphthyridine (230 mg, 1.26 mmol) in Dioxane (20 mL) was added 4-fluorobenzamide (175.26 mg, 1.26 mmol), Pd2(dba)3(173.03 mg, 0.19 mmol) and Xantphos (109.33 mg, 0.19 mmol), K2CO3(522.29 mg, 3.78 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 100%) to give 4-fluoro-N-(6-fluoro-1,8-naphthyridin-2- yl)benzamide (43 mg, 11.96% yield) as a white solid. LCMS: tR= 1.169 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 285.95 [M+H]+1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 9.07 (d, J = 3.1 Hz, 1H), 8.51 (s, 2H), 8.35 (dd, J = 8.4, 3.1 Hz, 1H), 8.24 – 8.14 (m, 2H), 7.42 – 7.33 (m, 2H). 19F NMR (377 MHz, DMSO) δ -107.64 (s, 1F), -129.55 (s, 1F). Synthesis of UP-033 Compound UP-033: To a solution of N-(5-chloro-1,8-naphthyridin-2-yl)-4- fluorobenzamide (90 mg, 0.2983 mmol) in DMSO (3 mL) was added Potassium fluoride (KF) (34.66 mg, 0.5966 mmol), Tetramethylammonium chloride (6.54 mg, 0.0596 mmol) slowly at 20 oC under N2. The mixture was heated at 120 oC for 3 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 100%) to give 4-fluoro-N-(5-fluoro-1,8-naphthyridin-2-yl)benzamide (31 mg, 21.86% yield) as a white solid. LCMS: tR= 1.403 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 280.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.98 (s, 1H), 9.01 (dd, J = 4.2, 1.9 Hz, 1H), 8.54 – 8.48 (m, 2H), 8.42 (dd, J = 8.0, 1.9 Hz, 1H), 7.54 (dd, J = 8.0, 4.3 Hz, 1H), 6.61 (s, 1H), 2.03 – 1.93 (m, 1H), 0.98 (d, J = 6.4 Hz, 2H), 0.77 (s, 2H). Synthesis of UP-035

[0038] Compound UP-035: To a mixture of compound 1 (50 mg, 0.239 mmol), compound 2 (33.2 mg, 0.239 mmol), Xantphos (5.48 mg, 0.005 mmol) and Cs2CO3(233 mg, 0.717 mmol) in dioxane (2 mL) was added Pd2(dba)3(5.54 mg, 0.009 mmol) under N2, the mixture was stirred at 100°C for 16 hours. The mixture was diluted with saturated aq. NH4Cl (10.0 mL) and extracted with dichloromethane (10 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0- 6%) to give UP-035 (49.94 mg, 75.4% yield) as white solid. LCMS: tR= 0.808 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 268.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.26 (s, 1H), 8.59 – 8.45 (m, 3H), 8.23 – 8.12 (m, 2H), 7.90 (d, J = 5.6 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H). Synthesis of UP-036

[0039] Compound UP-036: To a solution of 2-bromo-1,6-naphthyridine (150 mg, 0.72 mmol) in Dioxane (10 mL) was added 4-fluorobenzamide (99.84 mg, 0.72 mmol), Pd2(dba)3(98.57 mg, 0.11 mmol) and Xantphos (62.28 mg, 0.11 mmol), K2CO3(297.53 mg, 2.15 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and e8xtracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 4-fluoro-N-(1,6- naphthyridin-2-yl)benzamide (9 mg, 4.70% yield) as a white solid. LCMS: tR= 0.892 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 268.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.30 (s, 1H), 8.69 (d, J = 5.9 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H), 8.17 (dd, J = 8.7, 5.5 Hz, 2H), 7.74 (d, J = 5.9 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H). Synthesis of UP-038 Scheme 1. Synthetic route of UP-038 Compound 3: To a solution of 2-(4-bromoimidazol-1-yl)pyridine (1.2 g, 5.4 mmol) in dry THF (10 mL) was added t-BuLi (1.3 M in hexane, 6.2 mL, 8.1 mmol) dropwise at -78 °C under an atmosphere of N2. After addition, the solution was stirred at - 78 °C for 30 minutes. Then 4-fluorobenzaldehyde (0.80 g, 6.4 mmol) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The final mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic phases / layers were washed with water and brine, dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give (4-fluorophenyl)[1- (pyridin-2-yl)imidazol-4-yl]methanol (503 mg, 35.19% yield) as a yellow oil. LCMS: tR= 0.770 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 270.00 [M+H]+ Compound UP-038: To a solution of (4-fluorophenyl)[1-(pyridin-2-yl)imidazol- 4-yl]methanol (100 mg, 0.37 mmol) in DCM (5 mL) was added Dess-Martin periodinane (157.53 mg, 0.37 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 2-{4-[(4- fluorophenyl)carbonyl]imidazol-1-yl}pyridine (10.47 mg, 10.55% yield) as a white solid. LCMS: tR= 1.131 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 268.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 3.7 Hz, 1H), 8.25 (dd, J = 8.8, 5.7 Hz, 2H), 8.02 (td, J = 7.8, 1.8 Hz, 1H), 7.95 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 7.4, 4.9 Hz, 1H), 7.43 – 7.36 (m, 3H). Synthesis of UP-040 UP-040: To a solution of 2-(3-bromopyrazol-1-yl)pyridine (100 mg, 0.45 mmol) in dioxane (3 mL) was added 4-fluoroaniline (49.59 mg, 0.45 mmol), tBuONa (128.67 mg, 1.34 mmol), BrettPhos (35.93 mg, 0.07 mmol) and Pd(OAc)2(15.03 mg, 0.07 mmol) at 25 under N2. The mixture was heated at 140 for 1 hours. Then the reaction mixturewas concentrated in vacuo, the residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% NH4OH) to give the pure product (23.86 mg, 20.82% yield) as a white solid. LCMS: tR= 1.393 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 255.00 [M+H]+1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.39 (m, 1H), 8.03 – 7.88 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.62 – 7.52 (m, 2H), 7.23 (m, 1H), 7.11 (t, J = 8.9 Hz, 2H), 6.11 (d, J = 2.7 Hz, 1H). Synthesis of UP-042 Compound UP-042: To a mixture of compound 1 (200 mg, 0.829 mmol), compound 2 (92.1 mg, 0.829 mmol), DavePhos (19.5 mg, 0.049 mmol) and KOtBu (279 mg, 2.48 mmol) in toluene (3 mL) was added Pd2(dba)3(18.9 mg, 0.0207 mmol) under N2, the mixture was stirred at 80 °C for 16 hours. The mixture was diluted with saturated aq. NH4Cl (10.0 mL) and extracted with ethyl acetate (10 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-6%) and purified by prep-HPLC (Column: Shim-pack, Mobile phase: acetonitrile / water (0.1% TFA), Gradient: 60-70%) to give UP-042 (86.05 mg, 37.4% yield) as yellow solid. LCMS: tR= 0.877 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 272.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.03 (t, J = 7.6 Hz, 1H), 7.81 – 7.74 (m, 2H), 7.68 (s, 1H), 7.48 – 7.41 (m, 1H), 7.20 (t, J = 8.8 Hz, 2H). Synthesis of UP-043 Compound UP-043 : To a mixture of compound 1 (200 mg, 0.829 mmol),compound 2 (125 mg, 0.829 mmol), Xantphos (19.2 mg, 0.033 mmol) and Cs2CO3(810.8 mg, 2.488 mmol) in dioxane (3 mL) was added Pd2(dba)3(18.99 mg, 0.0207 mmol) under N2, the mixture was stirred at 120 °C for 1 hour under microwave. The mixture was diluted with saturated aq. NH4Cl (10.0 mL) and extracted with dichloromethane (10 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-6%) to give UP-043 (60.88 mg, 23.3% yield) as white solid. LCMS: tR= 0.883 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 312.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.69 – 8.57 (m, 1H), 8.09 – 8.03 (m, 1H), 7.98 – 7.88 (m, 3H), 7.70 – 7.62 (m, 1H), 7.49 – 7.41 (m, 1H), 7.39 – 7.33 (m, 1H), 5.34 – 5.14 (m, 2H). Synthesis of UP-045

[0040] Compound UP-045: To a mixture of compound 1 (100 mg, 0.564 mmol) and TEA (114 mg, 1.12 mmol) in DCM (2 mL) was added compound 2 (89.4 mg, 0.564 mmol) at 0°C, the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-6%) and purified by prep-HPLC (Column: Gemini, Mobile phase: ACN---H2O (0.1%TFA), Gradient: 25-60%) to give UP-045 (35.81 mg, 20.9% yield) as white solid. LCMS: tR= 0.868 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 300.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.63 (d, J = 4.0 Hz, 1H), 8.22 (dd, J = 8.8, 5.6 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.47 – 7.35 (m, 3H). Synthesis of UP-046

[0041] Compound 3: To a solution of (3-chloro-4-fluorophenyl)thiourea (80 mg, 0.39 mmol) in MeOH(1 mL) was added 2-bromo-1-(2-nitrophenyl)ethanone (95.40 mg, 0.39 mmol) at 25under N2. The mixture was stirred at 25 for 2 hours. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 20% to 30%) to give N-(3-chloro- 4-fluorophenyl)-4-(2-nitrophenyl)-1,3-thiazol-2-amine (140 mg, 97.50% yield) as a yellow solid. LCMS: tR= 1.490 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 350.00 [M+H]+ UP-046: To a solution of N-(3-chloro-4-fluorophenyl)-4-(2-nitrophenyl)-1,3-thiazol-2- amine (140 mg, 0.40 mmol) in EtOH / H2O=5:1 (2 mL) was added NH4Cl (106.98 mg, 2.0 mmol) and Fe (111.70 mg, 2.0 mmol) at 25 under N2. The mixture was heated at 80 for 2 hours. Then the reaction mixture was concentrated in vacuo, the residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% NH4OH) to give the pure product (25 mg, 23.32% yield) as a white solid. LCMS: tR= 0.989 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 269.00 [M+H]+1H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 7.94 (d, J = 6.6 Hz, 1H), 7.41 (m, 3H), 7.10 – 7.01 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 7.5 Hz, 1H), 5.82 (s, 2H). Synthesis of UP-047 Compound 3: To a solution of 2-chloro-8-nitroquinoline (500 mg, 2.40 mmol) in 1,4-dioxane (10 mL) was added 4-fluorobenzamide (333.47 mg, 2.40 mmol), Cs2CO3(2342.87 mg, 7.19 mmol), Xantphos (207.81 mg, 0.36 mmol) and PD2(DBA)3(329.23 mg, 0.36 mmol) at 25 under N2. The mixture was heated at 100 for 16 hours. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 20% to 30%) to give 4-fluoro-N-(8-nitroquinolin-2-yl)benzamide (800 mg, 91.14% yield) as a yellow solid. LCMS: tR= 1.371 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 312.15 [M+H]+ Compound 4: To a solution of 4-fluoro-N-(8-nitroquinolin-2-yl)benzamide (300 mg, 0.96 mmol) in MeOH (5 mL) was added Pd / C (30.77 mg, 0.29 mmol). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. Then the mixture was filtered through celite and concentrated under vacuum to give crude N-(8-aminoquinolin- 2-yl)-4-fluorobenzamide (200 mg, 73.77% yield) which was used directly in next step without further purification. LCMS: tR= 1.248 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 282.10 [M+H]+ UP-046: To a solution of N-(8-aminoquinolin-2-yl)-4-fluorobenzamide (100 mg, 0.36 mmol) in DCM (2 mL) was added TEA (107.92 mg, 1.07 mmol) and Ac2O (54.44 mg, 0.53 mmol) at 25 under N2. The mixture was stirred at 25 for 2 hours. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 20% to 30%) to give N-(8-acetamidoquinolin-2-yl)-4-fluorobenzamide (70 mg, 60.28% yield) as a white solid. LCMS: tR= 1.698 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 324.05 [M+H]+1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.80 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.41 (dd, J = 21.8, 9.0 Hz, 2H), 8.19 – 8.09 (m, 2H), 7.66 – 7.57 (m, 1H), 7.45 (m, 3H), 2.28 (s, 3H). Synthesis of UP-048 Compound 3: To a solution of 2-chloro-8-nitroquinoline (600 mg, 2.88 mmol) in dioxane / H2O=5 / 1 (10 mL) was added tert-butyl [2-(dihydroxyboranyl)-5-fluoroindol-1- yl] formate (966.71 mg, 3.45 mmol), DIPEA (1.12 g, 8.63 mmol), and XPhos Pd G2 (226.08 mg, 0.29 mmol) under an atmosphere of N2, the solution was stirred at 60 for 2hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 2% to 3%) to give tert-butyl [5-fluoro- 2-(8-nitroquinolin-2-yl)indol-1-yl] formate (850 mg, 68.74% yield) as a yellow solid. LCMS: tR= 1.638 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 408.15 [M+H]+ Compound 4: To a solution of tert-butyl [5-fluoro-2-(8-nitroquinolin-2-yl)indol-1-yl] formate (300 mg, 0.73 mmol) in MeOH (10 mL) was added Pd / C (31.07 mg, 0.29 mmol). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. Then the mixture was filtered through celite and concentrated under vacuum to give crude [2-(8- aminoquinolin-2-yl)-5-fluoroindol-1-yl] tert-butyl formate (210 mg, 71.77% yield) which was used directly in next step without further purification. LCMS: tR= 1.697 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 378.05 [M+H]+ Compound 5: To a solution of [2-(8-aminoquinolin-2-yl)-5-fluoroindol-1-yl] tert-butyl formate (200 mg, 0.53 mmol) in DCM (3 mL) was added TEA (160.44 mg, 1.59 mmol), Ac2O (80.93 mg, 0.79 mmol) at 25 under N2. The mixture was stirred at 25 for 3 hours. Then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 20% to 30%) to give tert-butyl [2-(8- acetamidoquinolin-2-yl)-5-fluoroindol-1-yl] formate (320 mg, 97.92% yield) as a yellow oil. LCMS: tR= 1.693 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 420.10 [M+H]+ UP-048: To a solution of tert-butyl [2-(8-acetamidoquinolin-2-yl)-5-fluoroindol-1-yl] formate (100 mg, 0.24 mmol) in ACOH (1 mL) under an atmosphere of N2, the solution was stirred at 100 for 16 hours. Then the reaction mixture was concentrated in vacuo, the residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to give the N-[2-(5- fluoro-1H-indol-2-yl)quinolin-8-yl]acetamide (20 mg, 26.07% yield) as a yellow solid. LCMS: tR= 1.917 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 320.05 [M+H]+1H NMR (400 MHz, DMSO) δ 12.23 (s, 1H), 10.27 (s, 1H), 8.72 (d, J = 6.7 Hz, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.65 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 1.3 Hz, 1H), 7.31 (dd, J = 10.0, 2.1 Hz, 1H), 6.95 (m, 1H), 2.43 (s, 3H). Synthesis of UP-049

[0042] Compound 3: To a solution of tert-butyl [2-(dihydroxyboranyl)-5-fluoroindol-1- yl] formate (70 mg, 0.25 mmol) in Dioxane / H2O=4:1 (10 mL) was added 2-chloro-7H- 1,7-naphthyridin-8-one (45.13 mg, 0.25 mmol), X-phos Pd G2 (19.64 mg, 0.25mmol) and DIPEA (64.59 mg, 0.50 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 4 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give tert-butyl [5-fluoro-2-(8-oxo-7H-1,7- naphthyridin-2-yl)indol-1-yl] formate (71 mg, 74.67% yield) as a white solid. LCMS: tR= 1.323 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 380.00 [M+H]+

[0043] Compound UP-049: A solution / mixture of tert-butyl [5-fluoro-2-(8-oxo-7H-1,7- naphthyridin-2-yl)indol-1-yl] formate (35 mg, 0.09 mmol) in HCl EtOAc solution (4M, 8 mL) and DCM (2 mL), MeOH (2 mL) was stirred at room temperature for 8 hours. The mixture was concentrated under reduced pressure. The residue was triturated in PE / EtOAc, filtered, and dried under vacuum to provide 2-(5-fluoro-1H-indol-2-yl)-7H- 1,7-naphthyridin-8-one (10.2 mg, 39.67% yield) as a HCl salt. LCMS: tR= 1.193 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 280.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.65 (d, J = 28.0 Hz, 2H), 8.28 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 8.8, 4.7 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.27 (s, 2H), 7.00 (td, J = 9.2, 2.5 Hz, 1H), 6.58 (d, J = 7.0 Hz, 1H). Synthesis of UP-050 Scheme 1. Synthetic route of UP-050 Compound 2: To a solution of compound 1 (1.94 g, 0.0131 mol) in DMF (20 mL) was added NaH (0.63 g, 0.0157 mol) at 0°C, the mixture was stirred at 0°C for 0.5 hour. Then, PMBCl (3.08 g, 0.0196 mol) was added in the mixture at 0°C, the mixture was stirred at 20°C for 1.5 hours. The mixture was quenched with water (20mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-60%) to give compound 2(2.20 g, 56.4% yield) as red solid. 1H NMR (400 MHz, DMSO-d6) δ 8.62 – 8.55 (m, 1H), 7.74 (dd, J = 7.6, 0.8 Hz, 1H), 7.47 (dd, J = 7.6, 4.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.65 (s, 2H), 3.73 (s, 3H), 3.48 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H). Compound : To a solution of compound 2 (2.00 g, 0.0075 mol) in DCM (20 mL) was added m-CPBA (1.42 g, 0.0082 mol) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-6%) to give compound 3 (1.86 g, 78.6% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 6.4 Hz, 1H), 7.40 – 7.34 (m, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.59 (s, 2H), 3.74 (s, 3H), 3.49 – 3.38 (m, 2H), 2.85 (t, J = 6.0 Hz, 2H). Compound 4: To a solution of compound 3 (500 mg, 1.75 mmol) in POCl3(5 mL), the mixture was stirred at 80°C for 3 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-10%) to give compound 4 (180 mg, 30.3% yield) as yellow oil. LCMS: tR= 1.151 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 303.05 [M+H]+ Compound 6: To a mixture of compound 4 (100 mg, 0.231 mmol), compound 5 (97.1 mg, 0.346 mmol) and DIPEA (89.4 mg, 0.693 mmol) in dioxane / H2O=10:1 (1 mL) was added X-phos Pd G2 (27.2 mg, 0.0346 mmol) under N2, the mixture was stirred at 100°C for 2 hours under microwave. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product compound 6 (100 mg, crude) as yellow oil was used for the next step without any purification. LCMS: tR= 1.694 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 402.15 [M+H]+

[0044] Compound UP-050: To a solution of compound 6 (100 mg, 0.199 mmol) in TFA (1 mL) was added TfOH (0.1 ml), the mixture was stirred at 20°C for 4 hours. The mixture was concentrated under reduced pressure to remove the solvent. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: ACN-H2O (0.05%NH3, Gradient: 35-60%) to give UP-050 (7.94 mg, 13.6% yield) as white solid. LCMS: tR= 1.394 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 281.95 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.24 (s, 1H), 7.70 (d, J = 5.2 Hz, 1H), 7.46 (dd, J = 8.8, 4.4 Hz, 1H), 7.38 (dd, J = 9.6, 2.4 Hz, 1H), 7.03 (td, J = 9.6, 2.4 Hz, 1H), 6.80 (s, 1H), 3.35 (s, 2H), 3.21 (t, J = 6.4 Hz, 2H). Synthesis of UP-051&UP-052 Scheme 1. Synthetic route of UP-052

[0045] Compound UP-052: To a mixture of compound 1 (50 mg, 0.276 mmol), compound 2 (77.0 mg, 0.553 mmol), K2CO3(114 mg, 0.830 mmol) and Xantphos (24.0 mg, 0.0415 mmol) in dioxane (3 mL) was added Pd2(dba)3(38.0 mg, 0.0415 mmol), the mixture was stirred at 110°C for 1 hour under microwave. The mixture was diluted with water(20 mL) and the mixture was filtered and collected the filter cake to give UP-052 (15.78 mg, 14.4% yield) as yellow solid. LCMS: tR= 0.980 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 284.10 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.27 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.24 – 8.11 (m, 3H), 7.37 (t, J = 8.8 Hz, 2H), 7.25 (d, J = 6.4 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H). Compound UP-051: To a solution of UP-052 (40 mg, 0.141 mmol) in EtOH (4 mL) was added Pd / C (1.5 mg, 0.014 mmol) and AcOH (4 mL) under H2(15Psi), the mixture was stirred at 50°C for 12 hours. The mixture was filtered (with celite) and collected the filtrate and concentrated under reduced pressure. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: acetonitrile / water (0.1% FA), Gradient: 30-60%) to give UP-051 (1.4 mg, 3.33% yield) a white solid. LCMS: tR= 0.970 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 286.15 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.12 (dd, J = 8.8, 5.6 Hz, 3H), 7.83 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 8.8 Hz, 2H), 3.40 (dd, J = 6.4, 3.6 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H). Synthesis of UP-053 Compound UP-053: To a solution of N-(6-aminopyridin-2-yl)acetamide (100 mg, 0.66 mmol) in DCM (5 mL) was added benzoyl chloride (111.58 mg, 0.79 mmol), TEA (100.41 mg, 0.99 mmol) slowly at 0 °C under N2. The mixture was heated at 20 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford N- (6-acetamidopyridin-2-yl)benzamide (46.3 mg, 27.42% yield) as a white solid. LCMS: tR= 1.364 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 256.05 [M+H]+1H NMR (400 MHz, DMSO-d) δ 10.34 (s, 1H), 10.21 (s, 1H), 8.01 – 7.94 (m, 2H), 7.87 – 7.73 (m, 3H), 7.61 (dd, J = 8.4, 6.2 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 2.11 (s, 3H). Synthesis of UP-054

[0046] Compound 3: To a solution of N-(6-bromopyridin-2-yl)acetamide (100 mg, 0.46 mmol) in Dioxane / H2O=4:1 (10 mL) was added tert-butyl [2-(dihydroxyboranyl)indol-1- yl] formate (146.25 mg, 0.56 mmol), XPhos Pd G2 (54.82 mg, 0.07 mmol) and DIPEA (180.29 mg, 1.40 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give tert-butyl [2-(6-acetamidopyridin-2-yl)indol-1-yl] formate (151 mg, 92.15% yield) as a white solid. LCMS: tR= 1.503 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 352.05 [M+H]+ Compound UP-054: To a solution of tert-butyl [2-(6-acetamidopyridin-2- yl)indol-1-yl] formate (100 mg, 0.28 mmol) in AcOH (2 mL) slowly at 20 °C under N2. The mixture was heated at 100 °C for 4 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep- HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford N-[6-(1H-indol-2-yl)pyridin-2-yl]acetamide (34.12 mg, 47.85% yield) as a white solid. LCMS: tR= 1.245 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 252.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 10.36 (s, 1H), 7.93 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.17 – 7.09 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 2.15 (s, 3H). Synthesis of UP-055 Compound 3: To a solution of 6-bromo-5-methylpyridin-2-amine (2 g, 0.01 mol) in DCM (20 mL) was added TEA (3.25 g, 0.03 mol) dropwise at 0 under an atmosphere of N2. After addition, the solution was stirred at 0 for 1 hours. Then benzoyl chloride (1.50 g, 0.01 mol) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 15 hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 20% to 30%) to give N-(6-bromo-5-methylpyridin-2-yl)benzamide (1.3 g, 42.06% yield) as a white solid. LCMS: tR= 1.402 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 292.00 [M+H]+ UP-055: To a solution of N-(6-bromo-5-methylpyridin-2-yl)benzamide (100 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added acetamide (20.29 mg, 0.34 mmol), K2CO3(142.21 mg, 1.03 mmol), xantphos (29.78 mg, 0.05 mmol) and PD2(DBA)3(47.18 mg, 0.05 mmol) at 25 under N2. The mixture was heated at 100 for 16 hours. Then the reaction mixture was concentrated in vacuo, the residue was further purified by prep- HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% NH4OH) to give the pure product (37.08 mg, 39.68% yield) as a white solid. LCMS: tR= 0.924 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 270.05 [M+H]+1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.90 (s, 1H), 8.07 – 7.97 (m, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.58 (m, 1H), 7.50 (m, 2H), 2.14 (s, 3H), 2.05 (s, 3H). Synthesis of UP-056 Scheme 1. Synthetic route of UP-056 Compound 3: To a mixture of compound 1 (1 g, 0.0062 mol), compound 2 (1.62 g, 0.0062 mol) and Na2CO3(1.97 g, 0.0186 mol) in dioxane / H2O=10 / 1 (20 mL) was added Pd(dppf)Cl2DCM (0.05 g, 0.0001 mol) under N2, the mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-3%) to give compound 3 (1.4 g, 59.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.6, 3.6 Hz, 1H), 7.44 – 7.35 (m, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.01 (s, 1H), 2.40 (s, 3H), 1.31 (s, 9H). Compound 5: To a mixture of compound 3 (100 mg, 0.290 mmol), compound 4 (17.1 mg, 0.290 mmol), K2CO3(120 mg, 0.872 mmol) and Pd2(dba)3(39.94mg, 0.0436 mmol) in dioxane (2 mL) was added Xantphos (25.2 mg, 0.0436 mmol), the mixture was stirred at 100°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-6%) to give compound 5 (80 mg, 67.5% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 6.91 (s, 1H), 2.21 (s, 3H), 2.05 (s, 3H), 1.24 (d, J = 6.5 Hz, 9H). Compound UP-056: To a solution of compound 5 (70 mg, 0.191 mmol) in AcOH (1 mL), the mixture was stirred at 100°C for 4 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: ACN--H2O (0.1%FA), Gradient: 30-70%) to give UP-056 (22.19 mg, 42.0% yield) as white solid. LCMS: tR= 1.155 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 266.20 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 10.02 (s, 1H), 7.76 (dd, J = 21.2, 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.16 – 7.04 (m, 2H), 7.00 (t, J = 7.0 Hz, 1H), 2.19 (s, 3H), 2.11 (s, 3H). Synthesis of UP-057 Scheme 1. Synthetic route of UP-057 Compound 3: To a solution of 6-aminopyridine-2-carbonitrile (1 g, 8.4 mmol) in DCM (25 mL) was added benzoyl chloride (1.30 g, 9.24 mmol), TEA (1.27 g, 12.6 mmol) slowly at 0 °C under N2. The mixture was heated at 20 °C for 2 hours. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give N-(6-cyanopyridin-2-yl)benzamide (1.31 g, 70.24% yield) as a white solid. LCMS: tR= 1.201 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 224.00 [M+H]+ Compound UP-057: To a solution of N-(6-cyanopyridin-2-yl)benzamide (100 mg, 0.45 mmol) in DMSO (2 mL) was added Hydrogen peroxide (18.28 mg, 0.54 mmol), K2CO3(9.29 mg, 0.07 mmol) slowly at 0 °C under N2. The mixture was heated at 20 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 2-C- benzenepyridine-2,6-dicarboxamide (20 mg, 18.50% yield) as a white solid. LCMS: tR= 0.982 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 242.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.03 (t, J = 7.1 Hz, 3H), 7.90 (s, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 6.9 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H). Synthesis of UP-058 Scheme 1. Synthetic route of UP-058 Compound 3: To a mixture of compound 1 (100 mg, 0.497 mmol), compound 2 (130 mg, 0.497 mmol) and K2CO3(206.28 mg, 1.4925 mmol) in dioxane / H2O=10:1 (1 ml) was added Pd(dppf)Cl2(3.64 mg, 0.0049 mmol) under N2, the mixture was stirred at 80°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-5%) to give compound 2 (140 mg, 74.8% yield) as white solid. LCMS: tR= 1.340 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 337.75 [M+H]+ Compound UP-058: To a solution of compound 3 (50.0 mg, 0.147 mmol) in EtOAc (1 mL) was added HCl in EtOAc (1 mL), the mixture was stirred at 20°C for 2 hours. The mixture was diluted with ethyl acetate (5 mL). The mixture was filtered and collected the filter cake to give UP-058(20.54 mg, 57.9% yield) as yellow solid. LCMS: tR= 1.060 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 238.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.85 (s, 1H), 8.16 (d, J = 7.2 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H). Synthesis of UP-059 Compound 2: To a solution of ethyl (2E)-3-(3-amino-6-chloropyridazin-4- yl)prop-2-enoate (550 mg, 2.42 mmol) in MeOH (20 mL) was added 10% Pd / C (56.56 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. Then the mixture was filtered through celite, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 100%) to give methyl 3-(3- aminopyridazin-4-yl)propanoate (180 mg, 41.12% yield) as a yellow solid. LCMS: tR= 0.394min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 196.00 [M+H]+ Compound 3: To a solution of ethyl 3-(3-aminopyridazin-4-yl)propanoate (180 mg, 0.92 mmol) in MeOH (5 mL) was added Sodium methanolate (199.23 mg, 3.7 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 8 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with DCM / MeOH, 0% to 10%) to give 5H,6H,8H-pyrido[2,3-c]pyridazin-7-one (101 mg, 73.45% yield) as a brown solid. LCMS: tR= 0.398 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 150.00 [M+H]+ Compound 4: To a solution of 5H,6H,8H-pyrido[2,3-c]pyridazin-7-one (100 mg, 0.67 mmol) in ACN / H2O=1 / 1 (10 mL) was added Sodium persulfate (319.29 mg, 1.34 mmol), Copper(II) sulfate (10.7 mg, 0.07 mmol) slowly at 20 °C under N2. The mixture was heated at 75 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with DCM / MeOH, 0% to 20%) to give 8H-pyrido[2,3- c]pyridazin-7-one (21 mg, 21.28% yield) as a red solid. LCMS: tR= 0.382 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 148.00 [M+H]+ Compound 5: To a solution of 8H-pyrido[2,3-c]pyridazin-7-one (20 mg, 0.14 mmol) in POCl3(208.38 mg, 1.36 mmol) slowly at 20 °C under N2. The mixture was heated at 100 oC for 2 hours. The resulting mixture was diluted with ice water (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give 7-chloropyrido[2,3- c]pyridazine (15 mg, 66.67% yield) as a yellow solid. LCMS: tR= 0.712 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 166.15 [M+H]+ Compound UP-059: To a solution of 7-chloropyrido[2,3-c]pyridazine (15 mg, 0.09 mmol) in dioxane (2 mL) was added 4-fluorobenzamide (13.87 mg, 0.10 mmol), Pd2(DBA)3 (8.30 mg, 0.01 mmol) and Xantphos (5.24 mg, 0.01 mmol) and Cs2CO3(88.56 mg, 0.27 mmol) slowly at 20 °C under N2. The mixture was heated at 60 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give 4-fluoro-N-{pyrido[2,3-c]pyridazin-7-yl}benzamide (6.32 mg, 26.05% yield) as a yellow solid. LCMS: tR= 1.000 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 269.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.44 (d, J = 5.5 Hz, 1H), 8.67 (d, J = 9.1 Hz, 1H), 8.60 (d, J = 9.1 Hz, 1H), 8.28 (d, J = 5.4 Hz, 1H), 8.21 (dd, J = 8.8, 5.5 Hz, 2H), 7.40 (t, J = 8.8 Hz, 2H). Synthesis of UP-063 Compound UP-063: To a solution of 1,8-naphthyridin-2-amine (100 mg, 0.69 mmol) in DMF (5 mL) was added 2-methyl-5-phenylpyrazole-3-carboxylic acid (139.30 mg, 0.69 mmol), HATU (288.13 mg, 0.76 mmol), DIPEA (178.07 mg, 1.38 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 2- methyl-N-(1,8-naphthyridin-2-yl)-5-phenylpyrazole-3-carboxamide (9.57 mg, 4.22% yield) as a white solid. LCMS: tR= 1.235 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 330.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.05 (dd, J = 4.3, 2.0 Hz, 1H), 8.55 (d, J = 8.9 Hz, 1H), 8.51 – 8.45 (m, 2H), 7.88 (s, 1H), 7.84 – 7.78 (m, 2H), 7.60 (dd, J = 8.0, 4.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 4.20 (s, 3H). Synthesis of UP-064 Compound UP-064: To a solution of 1,8-naphthyridin-2-amine (55 mg, 0.38 mmol) in DMF (5 mL) was added 3-phenyl-1,2-oxazole-5-carboxylic acid (71.68 mg, 0.38 mmol), HATU (158.48 mg, 0.42mmol) and DIPEA (97.94 mg, 0.76 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 8 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% TFA) to afford N-(1,8-naphthyridin-2-yl)-3-phenyl- 1,2-oxazole-5-carboxamide (32.20 mg, 26.87% yield) as a white solid. LCMS: tR= 1.180 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 317.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ11 .92 (s, 1H), 9.07 (dd, J = 4.2, 1.9 Hz, 1H), 8.58 (d, J = 8.9 Hz, 1H), 8.52 – 8.43 (m, 2H), 8.14 (s, 1H), 7.92 (dd, J = 7.3, 2.2 Hz, 2H), 7.63 – 7.55 (m, 4H). Synthesis of UP-065

[0047] b UP-065: To a solution of 1-methyl-5-phenylpyrazole-3-carboxylic acid (100 mg, 0.49 mmol) in DMF (5 mL) was added 1,8-naphthyridin-2-amine (71.78 mg, 0.49 mmol), HATU (376.06 mg, 0.99 mmol), DIPEA (191.73 mg, 1.48 mmol) slowly at 25 under N2. The resulting solution was slowly warmed to 25 and stirred for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give 1-methyl-N-(1,8-naphthyridin-2-yl)-5-phenylpyrazole-3-carboxamide (70 mg, 42.55% yield) as a white solid. LCMS: tR= 1.595 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 330.05 [M+H]+1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.02 (dd, J = 4.3, 2.0 Hz, 1H), 8.53 (s, 2H), 8.43 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 (m, 2H), 7.54 (m, 4H), 7.14 (s, 1H), 4.02 (s, 3H). Synthesis of UP-066 Compound 2: To a solution of methyl 5-bromo-2H-1,2,4-triazole-3-carboxylate (2 g, 0.01 mol) in THF (20 mL) was added DIPEA (2.51 g, 0.02 mol) and PMBCl (1.82 g, 0.01 mol) under an atmosphere of N2, the solution was stirred at 50 for 16 hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 2% to 3%) to give methyl 5-bromo-2-(2- methoxy-5-methylphenyl)-1,2,4-triazole-3-carboxylate (1.3 g, 41.24% yield) as a white solid. LCMS: tR= 1.259 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 325.90 [M+H]+ Compound 4: To a solution of methyl 5-bromo-2-(2-methoxy-5-methylphenyl)-1,2,4-triazole-3- carboxylate (1.3 g, 4.00 mmol) in dioxane / H2O=5 / 1 (15 mL) was added phenylboranediol (0.59 g, 4.80 mmol), K3PO4(2.55 g, 12.0 mmol), Pd(dppf)Cl2.DCM (0.49 g, 0.60 mmol) under an atmosphere of N2, the solution was stirred at 60 for 2 hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 2% to 3%) to give methyl 2-(2-methoxy-5- methylphenyl)-5-phenyl-1,2,4-triazole-3-carboxylate (900 mg, 65.00% yield) as a brown solid. LCMS: tR= 1.717 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 324.05 [M+H]+ Compound 5: To a solution of methyl 2-(2-methoxy-5-methylphenyl)-5-phenyl-1,2,4-triazole-3- carboxylate (900 mg, 2.78 mmol) in EtOH / H2O=1:1 (56 mL) was add LiOH (133.31 mg, 5.57 mmol) under an atmosphere of N2, the solution was stirred at 25 for 16 hours. Then the reaction mixture was concentrated in vacuo. The combined organic phases / layers were washed with water and brine, dried with sodium sulfate, concentrated, and purified on a Biotage Isolera One (C18 column, eluting with 10% to 90% MeCN / H2O containing 0.1% formic acid) to provide 2-(2-methoxy-5-methylphenyl)-5- phenyl-1,2,4-triazole-3-carboxylic acid (800 mg, 83.63% yield) as a brown solid. LCMS: tR= 1.127 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 310.00 [M+H]+

[0048] Compound 7: To a solution of 2-(2-methoxy-5-methylphenyl)-5-phenyl-1,2,4-triazole-3- carboxylic acid (200 mg, 0.65 mmol) in DMF (5 mL) was add 1,8-naphthyridin-2-amine (93.86 mg, 0.65 mmol), HATU (491.73 mg, 1.29 mmol), DIPEA (250.70 mg, 1.94 mmol) under an atmosphere of N2. the solution was stirred at 25 for 16 hours. Then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 2% to 3%) to give 2-(2-methoxy-5- methylphenyl)-N-(1,8-naphthyridin-2-yl)-5-phenyl-1,2,4-triazole-3-carboxamide (80 mg, 28.37% yield) as a yellow solid. LCMS: tR= 1.773 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 437.05 [M+H]+ UP-066: To a solution of 2-(2-methoxy-5-methylphenyl)-N-(1,8-naphthyridin-2-yl)-5- phenyl-1,2,4-triazole-3-carboxamide (80 mg, 0.18 mmol) in DCM / TFA=1:1 (4 mL) under an atmosphere of N2, the solution was stirred at 50 for 16 hours. Then the reaction mixture was concentrated in vacuo, the residue was further purified by prep- HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% TFA) to give the N-(1,8-naphthyridin-2-yl)-5-phenyl-2H-1,2,4-triazole- 3-carboxamide (20 mg, 34.15% yield) as a white solid. LCMS: tR= 0.796 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 317.05 [M+H]+1H NMR (400 MHz, DMSO) δ 10 .56 (s, 1H), 9.07 (dd, J = 4.3, 1.9 Hz, 1H), 8.62 (m, 1H), 8.53 (m, 2H), 8.14 (m, 2H), 7.66 – 7.53 (m, 4H). Synthesis of UP-067 Scheme 1. Synthetic route of UP-067 UP-067: To a solution of 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid (100 mg, 0.45 mmol) in DMF (10 mL) was added 1,8-naphthyridin-2-amine (65.21 mg, 0.45 mmol), HATU (341.61 mg, 0.90 mmol), DIPEA (174.16 mg, 1.35 mmol) slowly at 25 under N2. The resulting solution was slowly warmed to 25 and stirred for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 50%) to give 5-(2-chlorophenyl)-N-(1,8-naphthyridin-2-yl)-2H-pyrazole-3- carboxamide (12 mg, 7.57% yield) as a white solid. LCMS: tR= 1.586 min in 5-95AB_3.0min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 350.00 [M+H]+1H NMR (400 MHz, DMSO) δ 14.07 (s, 1H), 9.03 (dd, J = 4.2, 1.9 Hz, 1H), 8.54 (s, 2H), 8.44 (dd, J = 8.1, 2.0 Hz, 1H), 7.79 (s, 1H), 7.62 (m, 1H), 7.59 – 7.55 (m, 1H), 7.51 (m, 3H). Synthesis of UP-068 Compound UP-068: To a solution of 1,8-naphthyridin-2-amine (60 mg, 0.41 mmol) in DMF (5 mL) was added 5-{3-[(difluoromethyl)-$l^{2}-fluoranyl]phenyl}-2H- pyrazole-3-carboxylic acid (106.30 mg, 0.41 mmol), HATU (172.87 mg, 0.45 mmol) and DIPEA (106.83 mg, 0.83 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 8 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 5-{3- [(difluoromethyl)-$l^{2}-fluoranyl]phenyl}-N-(1,8-naphthyridin-2-yl)-2H-pyrazole-3- carboxamide (13.41 mg, 8.44% yield) as a white solid. LCMS: tR= 1.252 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 384.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 14.22 (d, J = 46.1 Hz, 1H), 11.51-10.25 (s, 1H), 9.04 (s, 1H), 8.55 (s, 2H), 8.45 (d, J = 7.8 Hz, 1H), 8.15 (t, J = 49.5 Hz, 3H), 7.75 (s, 2H), 7.57 (dd, J = 7.7, 4.1 Hz, 1H). Synthesis of UP-069 Compound UP-069 : To a mixture of compound 1 (200 mg, 1.06 mmol),compound 2 (100 mg, 1.06 mmol) and HATU (484 mg, 1.27 mmol) in DMF (3 mL) was added DIPEA (411 mg, 3.18 mmol), the mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-6%) and purified by prep-HPLC (Column: Gemini, Mobile phase: acetonitrile / water (0.1% FA), Gradient: 30-50%) to give UP-069 (10.35 mg, 3.54% yield) as white solid. LCMS: tR= 1.128 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 265.15 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 14.09.13.77- (m, 1H), 10.98-9.55 (m, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.90 – 7.78 (m, 3H), 7.54-7.28 (m, 4H), 7.23 – 7.11 (m, 1H). Synthesis of UP-071 Scheme 1. Synthetic route of UP-071

[0049] Compound 3: To a solution of compound 1 (5 g, 0.0396 mol) in THF (100 mL) was added t-BuOK (7.29 g, 0.0649 mol) at 0°C, the mixture was stirred at 0°C for 0.1 hour. Then, compound 2 (7.29 g, 0.0498 mol) was added in the mixture, the mixture was stirred at 70°C for 5 hours. The crude product was used for the next step. LCMS: tR= 1.320 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 227.10 [M+H]+ Compound 4: To a solution of compound 3 (9 g, 0.0398 mol) in AcOH (8 mL) was added N2H4*H2O (2.77 g, 0.0553 mol), the mixture was stirred at 60°C for 6 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-4%) to give compound 4 (3 g, 30.4% yield) as white solid. LCMS: tR= 1.151 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 303.05 [M+H]+ Compound 5: To a solution of compound 4 (500 mg, 2.24 mmol) in THF (5 mL) was added NaOH (269 mg, 6.74 mmol) in H2O (2.5 mL), the mixture was stirred at 50°C for 12 hours. Adjusted pH of the mixture to 5~6 with HCl (1 M). The mixture was extracted with dichloromethane (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was used for the next step without any purification. Compound 5 (210 mg, crude) was obtained as a yellow solid. LCMS: tR= 0.923 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 195.05 [M+H]+ Compound UP-071: To a mixture of compound 5 (20 mg, 0.103 mmol), compound 6 (14.9 mg, 0.103 mmol) and HATU (47 mg, 0.123 mmol) in DMF (1 mL) was added DIPEA (39.86 mg, 0.309 mmol), the mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: ACN---H2O (0.1%TFA, Gradient: 20-70%) to give UP-071 (3.12 mg, 9.03% yield) as white solid. LCMS: tR= 0.984 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 322.15 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10 .25 (s, 1H), 9.06 (d, J = 2.8 Hz, 1H), 8.63 – 8.52 (m, 3H), 7.65 (dd, J = 8.0, 4.4 Hz, 1H), 6.75 (s, 1H), 2.73 (d, J = 15.2 Hz, 1H), 1.97 (d, J = 10.4 Hz, 2H), 1.83 – 1.60 (m, 4H), 1.44 – 1.32 (m, 4H). Synthesis of UP-072

[0050] Compound UP-072: To a solution of 1,8-naphthyridin-2-amine (100 mg, 0.69 mmol) in DMF (5 mL) was added 5-cyclopropyl-2H-pyrazole-3-carboxylic acid (104.82 mg, 0.69 mmol), HATU (288.13 mg, 0.76 mmol), DIPEA (178.07 mg, 1.38 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford 5- cyclopropyl-N-(1,8-naphthyridin-2-yl)-2H-pyrazole-3-carboxamide (50.35 mg, 26.17% yield) as a white solid. LCMS: tR= 1.403 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 280.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.98 (s, 1H), 9.01 (dd, J = 4.2, 1.9 Hz, 1H), 8.54 – 8.48 (m, 2H), 8.42 (dd, J = 8.0, 1.9 Hz, 1H), 7.54 (dd, J = 8.0, 4.3 Hz, 1H), 6.61 (s, 1H), 2.03 – 1.93 (m, 1H), 0.98 (d, J = 6.4 Hz, 2H), 0.77 (s, 2H). Synthesis of UP-073 Scheme 1. Synthetic route of UP-073

[0051] Compound 3: To a mixture of compound 1 (5 g.0.0262 mol), compound 2 (3.8 g, 0.0262 mol) and HATU 11.95 g, 0.00314 mol) in DMF (50 mL) was added DIPEA (10.14 g,0.0786 mol), the mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (50.0 mL) and filtered and collected the filter cake to give a white solid. The crude product was used for the next step without any purification. Compound 3 (4.4 g, crude) was obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.23 (s, 1H), 11.60 (s, 1H), 9.03 (dd, J = 4.4, 2.0 Hz, 1H), 8.47 (ddd, J = 13.2, 10.0, 5.6 Hz, 3H), 7.56 (dd, J = 8.0, 4.4 Hz, 2H) Compound 4: To a mixture of 5 compound 3 (4.4 g, 0.0138 mol) and Cs2CO3(5.4 g, 0.0165 mol) in DMF (50 mL) was added SEMCl (2.53 g, 0.0151 mol) at 0°C, the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-50%) to give compound 4 (3 g, 43.4% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1 0.47 (s, 1H), 9.02 (dd, J = 4.4, 2.0 Hz, 1H), 8.56 – 8.41 (m, 3H), 7.56 (dd, J = 8.0, 4.4 Hz, 1H), 7.29 (s, 1H), 5.60 (s, 2H), 3.66 (t, J = 8.0 Hz, 2H), 0.86 (t, J = 7.6 Hz, 2H), -0.04 (s, 9H). Compound 6: To a mixture of compound 4 (3 g, 0.0067 mol), compound 5 (1.37 g, 0.01 mol) and K2CO3(2.78 g, 0.0201 mol) in dioxane / H2O=10:1 (30 mL) was added X-phos Pd G2 (0.79 g, 0.001 mol) under N2, the mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-50%) to give compound 6 (2.7 g, 79.1% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.03 (dd, J = 4.0, 2.0 Hz, 1H), 8.54 (s, 2H), 8.44 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 – 7.48 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 5.57 (s, 2H), 3.72 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H), 0.87 (t, J = 8.0 Hz, 2H), -0.04 (d, J = 10.0 Hz, 9H). Compound UP-073: To a solution of compound 6 (2.7 g, 0.0059 mol) in DCM (20 mL) was added TFA (10 mL) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by recrystallization (Petroleum ether: ethyl acetate = 1:1, 100 mL) and Dichloromethane / Methanol = 10:1, 100 mL) stirred at 25°C for 2 hours to give UP- 073 (0.653 g, 33.9% yield) as white solid. LCMS: tR= 1.186 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 330.10 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 14.01 (d, J = 44.4 Hz, 1H), 11.8-9.89 (m, 1H), 9.04 (s, 1H), 8.63 – 8.49 (m, 2H), 8.45 (d, J = 8.0 Hz, 1H), 7.93 – 7.34 (m, 5H), 7.29 – 7.10 (m, 1H), 2.39 (s, 3H). Synthesis of UP-073 Compound 3: To a mixture of compound 1 (1 g.0.0052 mol), compound 2 (0.76 g, 0.0052 mol) and HATU 2.37 g, 0.0062 mol) in DMF (20 mL) was added DIPEA (2.02 g,0.156 mol), the mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (30.0 mL) and filtered and collected the filter cake to give a white solid. The crude product was used for the next step without any purification. Compound 3 (1.1 g, crude) was obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.22 (s, 1H), 11.61 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 20.0, 8.8 Hz, 2H), 8.46 – 8.39 (m, 1H), 7.57 (dd, J = 8.0, 4.4 Hz, 1H), 7.54 (s, 1H). Compound 4: To a mixture of 5 compound 3 (680 mg, 2.13 mmol) and Cs2CO3(1044 mg, 3.20 mmol) in DMF (10 mL) was added SEMCl (392 mg, 2.35 mmol) at 0°C, the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-30%) to give compound 4 (660 mg, 61.8% yield) as white solid. LCMS: tR= 1.168 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 449.95 [M+H]+ Compound 6: To a mixture of compound 4 (20 mg, 0.0445 mmol), compound 5 (12.1 mg, 0.089 mmol) and K2CO3(18.4 mg, 0.133 mmol) in dioxane / H2O=10:1 (2 mL) was added X-phos Pd G2 (5.25 mg, 0.0066 mmol) under N2, the mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was used for the next step without any purification. Compound 6 (30 mg, crude) was obtained as brown oil. LCMS: tR= 1.715 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 460.15 [M+H]+ Compound UP-073: To a solution of compound 6 (30 mg, 0.0651 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: acetonitrile / water (0.1% TFA), Gradient: 35-60%) to give UP-073 (8.01 mg, 35.7% yield) as yellow solid. LCMS: tR= 0.963 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 330.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.4, 2.0 Hz, 1H), 8.62 – 8.48 (m, 3H), 7.70 (s, 1H), 7.62 (dt, J = 9.6, 6.4 Hz, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H). Synthesis of UP-075 Compound UP-075: To a mixture of compound 1 (90 mg.0.475 mol), compound 2 (82.8 mg, 0.570 mmol) and HATU 217 mg, 0.570 mmol) in DMF (2 mL) was added DIPEA (184 mg,1.42 mmol), the mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (20 mL). The mixture was filtered and collected the filter cake to give a white solid. UP-075 (42.51 mg, 27.9% yield) was obtained as white solid. LCMS: tR= 0.645 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 317.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 14.57-14.15 (m, 1H), 11.73-10.21 (m, 1H), 9.04 (s, 1H), 8.68 (s, 2H), 8.54 (s, 2H), 8.45 (dd, J = 8.0, 1.6 Hz, 1H), 8.15 – 7.64 (m, 3H), 7.57 (dd, J = 8.0, 4.0 Hz, 1H). Synthesis of UP-076 Compound 3: To a mixture of compound 1 (80 mg, 0.178 mmol), K2CO3(73.8 mg, 0.543 mmol) and Pd(dppf)Cl2(19.5 mg, 0.0267 mmol) in dioxane / H2O=10:1 (2 mL) was added compound 2 (22.4 mg, 0.142 mmol) under N2at 80°C, the mixture was stirred at 80°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-5%) to give compound 3 (100 mg, 58.2% yield) as yellow oil. LCMS: tR= 1.987 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 481.05 [M+H]+ Compound UP-076: To a solution of compound 3 (50 mg, 0.103 mmol) in DCM (1 mL) was added TFA (0.5 mL) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: ACN---H2O (0.1%TFA, Gradient: 20-60%) to give UP-076 (13.14 mg, 36.1% yield) as white solid. LCMS: tR= 1.028 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 351.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.12 – 8.99 (m, 1H), 8.60 – 8.48 (m, 4H), 8.11-7.74 (m, 3H), 7.63 – 7.58 (m, 1H). Synthesis of UP-077 Scheme 1. Synthetic route of UP-077 Compound 3: To a solution of 1-cyclopentylethanone (5 g, 0.0446 mol) in THF (60 mL) was added potassium t-butoxide (8.01 g, 0.0713 mol), diethyl oxalate (8.15 g, 0.0557 mol), the mixture was stirred at 80 for 10 h, the mixture was cooled to room temperature, hydrazine hydrate (8 g, 0.624 mol), AcOH (5.36 g, 0.0892 mol), the mixture was stirred at 80 °C for 3 h. The mixture was diluted with H2O and extracted with dichloromethane, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane / methanol= 1 / 1) to give the Compound 3 (3.2 g, 35.87% yield) as a yellow solid. LCMS: tR= 0.943 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 181.2 [M+H]+ Compound UP-077: To a solution of 5-cyclopentyl-2H-pyrazole-3-carboxylic acid (80 mg, 0.4439 mmol) was added 1,8-naphthyridin-2-amine (70.88 mg, 0.4882 mmol), HATU (202.54 mg, 0.5326 mmol) and DIEA (86.05 mg, 0.6058 mmol), the mixture was stirred at 25 °C for 10 h. The mixture was diluted with H2O and extracted with dichloromethane, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the UP-077 (25 mg, 17.41% yield) as a white solid. LCMS: tR= 1.098 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 308.1 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 13.37 (s, 1H), 10.00 (s, 1H), 9.00 (s, 1H), 8.51 (s, 2H), 8.42 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 6.71 (s, 1H), 3.12 (s, 1H), 2.05 (s, 2H), 1.69 (d, J = 43.2 Hz, 6H). Synthesis of UP-078 Scheme 1. Synthetic route of UP-078 Compound 3: To a solution of 1-cyclobutylethanone (5 g, 0.0509 mol) in THF (60 mL) was added potassium t-butoxide (9.14 g, 0.0814 mol), diethyl oxalate (9.3 g, 0.0636 mol), the mixture was stirred at 80 °C for 10 h, the mixture was cooled to room temperature, hydrazine hydrate (3.57 g, 0.0712 mol), AcOH (6.11 g, 0.1018 mol), the mixture was stirred at 80 °C for 3 h. The mixture was diluted with H2O and extracted with dichloromethane, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane / methanol= 1 / 1) to give the Compound 3 (2.2 g, 20.63% yield) as a yellow solid. LCMS: tR= 1.122 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 195.2 [M+H]+Compound 4: To a solution of ethyl 5-cyclobutyl-2H-pyrazole-3-carboxylate (160 mg, 0.8238 mmol) in EtOH (4 mL) was added NaOH (164.76 mg, 4.119 mmol) in H2O(1 mL).The mixture was stirred at 25 °C for 4 h. The mixture was diluted with H2O and added aqueous 1N HCl aq. to adjust pH~5 - 6, then extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure to give the Compound 4 (120 mg, 78.89% yield) as a white solid. LCMS: tR= 0.861 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 167.0 [M+H]+Compound UP-078: To a solution of 5-cyclobutyl-2H-pyrazole-3-carboxylic acid (60 mg, 0.3611 mmol) was added 1,8-naphthyridin-2-amine (57.66 mg, 0.3972 mmol), HATU (164.76 mg, 0.4333 mmol) and DIEA (70 mg, 0.5416 mmol), the mixture was stirred at 25 °C for 10 h. The mixture was diluted with H2O and extracted with dichloromethane, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the UP-078 (32 mg, 28.69% yield) as a white solid. LCMS: tR= 1.034 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 294.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 10.04 (s, 1H), 9.01 (dd, J = 4.2, 2.0 Hz, 1H), 8.52 (s, 2H), 8.44 (dd, J = 8.0, 2.0 Hz, 1H), 7.55 (dd, J = 8.0, 4.2 Hz, 1H), 6.79 (s, 1H), 3.60 – 3.54 (m, 1H), 2.39 – 2.28 (m, 2H), 2.24 – 2.11 (m, 2H), 2.05 – 1.94 (m, 1H), 1.91 – 1.83 (m, 1H). Synthesis of UP-079 Compound 3: To a solution of compound 1 (2.00 g, 0.0138 mol) in EtOH (40 mL) was added compound 2 (5.21 g, 0.0276 mol), the mixture was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-15%) to give compound 3 (1.8 g, 42.0% yield) a white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.70 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.89 (s, 1H), 5.23 (s, 2H), 3.78 (s, 3H).

[0052] Compound 5: To a mixture of compound 4 (100 mg, 0.688 mmol) and TEA (208 mg, 12.0 mmol) in THF (5 mL) was added BTC (67.4 mg, 0.227 mmol) at 0°C, the mixture was stirred at 0°C for 0.5 hour. Then, compound 3 (192 mg, 0.688 mmol) was added in the mixture, the mixture was stirred at 20°C for 12 hours. The mixture was quenched with MeOH (3 mL). The mixture was diluted with water (10.0 mL) and extracted with dichloromethane (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / Petroleum ether= 0-70%) to give compound 5 (100 mg, 30.2% yield) as yellow oil. LCMS: tR= 1.321 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 451.15 [M+H]+ Compound UP-079: To a solution of compound 5 (100 mg, 0.211 mmol) in TFA (1 mL) was added TfOH (0.1 mL) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: acetonitrile / water (0.1% TFA), Gradient: 25-60%) to give UP-079 (14.47 mg, 19.5% yield) as yellow solid. LCMS: tR= 0.883 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 331.10 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.44 (s, 1H), 9.06 – 8.98 (m, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.80 – 7.61 (m, 4H), 7.47 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 6.88 (s, 1H). Synthesis of UP-080 Compound 2: To a solution of {2-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5- phenylpyrazol-3-yl}methyl methanesulfonate (250 mg, 0.6518 mmol) in DMF (6 mL) was added NaN3 (84.73 mg, 1.3036 mmol), K2CO3(270.26 mg, 1.9554 mmol), the mixture was stirred at 50 °C for 2 h. The mixture was diluted with H2O and extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure to give the Compound 2 (160 mg, 69.09% yield) as a white solid. LCMS: tR= 1.693 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 330.2 [M+H]+

[0053] Compound 3: To a solution of 5-(azidomethyl)-1-[(2-methoxyethyl)trimethyl- $l^{5}-silyl]-3-phenylpyrazole (160 mg, 0.4841 mmol) in MeOH (8 mL) was added Pd / C (50 mg, 10%), the mixture was stirred at room temperature for 12 h under hydrogen atmosphere. The filtrate is separated by filtration, and then been concentrated under reduced pressure to give the Compound 3 (150 mg, 91.59% yield) as a white solid. LCMS: tR= 1.231 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 304.2 [M+H]+Compound 5: To a solution of {2-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5- phenylpyrazol-3-yl}methanamine (15 mg, 0.0493 mmol) in DMF (2 mL) was added 2- chloro-1,8-naphthyridine (9.74 mg, 0.0591 mmol), K2CO3(13.63 mg, 0.0986 mmol), KI (1.64 mg, 0.098 mmol), the mixture was stirred at 50 °C for 4 h. The mixture was diluted with H2O and extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate= 2 / 3) to give the Compound 5 (12 mg, 52.33% yield) as a white solid. LCMS: tR= 1.933 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 432.6 [M+H]+

[0054] Compound UP-080: To a solution of N-({2-[(2-methoxyethyl)trimethyl-$l^{5}- silyl]-5-phenylpyrazol-3-yl}methyl)-1,8-naphthyridin-2-amine (30 mg, 0.0693 mmol) in DCM (4 mL) was added trifluoroacetic acid (0.2 mL, 0.00175 mmol), the mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and purified by prep-HPLC to give the UP-080 (12 mg, 53.39% yield) as a white solid. LCMS: tR= 0.803 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 302.1 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.73 (s, 3H), 7.40 (s, 2H), 7.29 (s, 1H), 7.18 (dd, J = 7.6, 4.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 4.67 (s, 2H). Synthesis of UP-081 Scheme 1. Synthetic route of UP-081 Compound 6: To a mixture of compound 4 (50.0 mg, 0.111 mmol), compound 5 (38.8 mg, 0.222 mmol) and K2CO3(46.1 mg, 0.333 mmol) in dioxane / H2O=10:1 (3 mL) was added Pd(dppf)Cl2(12.2 mg, 0.016 mmol), the mixture was stirred at 80°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was used for the next step without any purification. Compound 6 (30 mg, crude) was obtained as brown oil. LCMS: tR= 1.356 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 498.05 [M+H]+ Compound UP-081: To a solution of compound 6 (30 mg, 0.0627 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: ACN--- H2O (0.1%TFA, Gradient: 25-60%) to give UP-081 (7.59 mg, 32.2% yield) as white solid. LCMS: tR= 1.008 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 368.00 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 9.05 (dd, J = 4.4, 1.6 Hz, 1H), 8.54 (dt, J = 13.6, 7.6 Hz, 3H), 8.07 (s, 1H), 7.86 (s, 1H), 7.80 – 7.51 (m, 3H). Synthesis of UP-083 Compound 2: To a mixture of compound 1 (100 mg, 0.462 mmol) in DMF (1 mL) was added NaH (22.2 mg, 0.555 mmol) at 0°C, the mixture was stirred at 0°C for 0.1 hour, then SEMCl (84.8 mg, 0.508 mmol) was added in the mixture at 0°C, the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was used for the next step without any purification. Compound 3 (150 mg, crude) was obtained as yellow oil. LCMS: tR= 1.653 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 347.05 [M+H]+ Compound 3: To a solution of compound 2 (150 mg, 0.431 mmol) in THF (1.5 mL) was added NaOH (51.7 mg, 1.29 mmol) in H2O (0.75 mL), the mixture was stirred at 50°C for 12 hours. Adjusted pH to 5~6 with HCl (1M). The mixture was diluted with water (10.0 mL) and extracted with dichloromethane (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was used for the next step without any purification. Compound 3 (150 mg, crude) was obtained as colorless oil. LCMS: tR= 1.101 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 319.10 [M+H]+ Compound 5: To a mixture of compound 3 (20 mg, 0.0626 mmol), compound 4 (13.6 mg, 0.0939 mmol) and HATU (28.5 mg, 0.0751 mmol) in DMF (1 mL) was added DIPEA (24.2 mg, 0.187 mmol), the mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Methanol / Dichloromethane= 0-5%) to give compound 5 (30 mg, 96.6% yield) as yellow oil. LCMS: tR= 1.009 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 332.90 [M+H]+

[0055] Compound UP-083: To a solution of compound 5 (30 mg, 0.0672 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0°C, the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. Then the crude product was purified by prep-HPLC (Column: Gemini, Mobile phase: acetonitrile / water (0.1% TFA), Gradient: 25-60%) to give UP-083 (3.4 mg, 15.5% yield) as yellow solid. LCMS: tR= 0.787 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 316.05 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.07 (d, J = 4.0 Hz, 1H), 8.68 – 8.52 (m, 3H), 8.27 (s, 1H), 8.11 (d, J = 7.2 Hz, 2H), 7.64 (dd, J = 7.6, 4.4 Hz, 1H), 7.57-7.43 (m, 3H). Synthesis of UP-084 Scheme 1. Synthetic route of UP-084

[0056] Compound 2: To a solution of ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (200 mg, 0.92 mmol) in THF / H2O = 1:1 (10 mL) was added sodium hydroxide (38.49 mg, 0.92 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 4 hours. Then the mixture was filtered through celite and concentrated under vacuum to give 5- phenyl-1,3,4-oxadiazole-2-carboxylic acid (162 mg, 92.94% yield) as a yellow solid. LCMS: tR= 0.898 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*30mm), MS (ESI) m / z = 191.00 [M+H]+ Compound UP-084: To a solution of 5-phenyl-1,3,4-oxadiazole-2-carboxylic acid (100 mg, 0.53 mmol) in DMF (5 mL) was added 1,8-naphthyridin-2-amine (76.34 mg, 0.53 mmol), HATU (219.96 mg, 0.58 mmol) and DIPEA (135.93 mg, 1.06 mmol) slowly at 20 °C under N2. The mixture was heated at 20 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% FA) to afford N-(1,8- naphthyridin-2-yl)-5-phenyl-1,3,4-oxadiazole-2-carboxamide (23.54 mg, 14.11% yield) as a white solid. LCMS: tR= 1.086 min in 5-95AB_2.5min_214&254_Shimadzu.lcm, chromatography (HALO C183.0*3...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR2a; X2is selected from N and CR2a; X3is selected from N and CR4; provided that at least one of X1, X2, and X3is N; R2, R2a, R3, and R4are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; and L1is selected from C(=O)NH, NHC(=O), NHC(=O)NH, and NHC(=O)O; or L1is absent; R1is selected from C1-6alkyl and Cy1, wherein said C1-6alkyl is optionally substituted with C1-6alkoxy, C1-6alkylamino, or Cy1; each Cy1is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with RCy1; and each RCy1is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, and carboxy; each Y1is independently selected from O, S, and NH; each Y2is independently selected from N and CR6b; each Y3is independently selected from N and CR5b; R5a, R5b, R6a, R6b, R7a, and R7bare each independently selected from H, NO2, OH, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino.

2. The compound of claim 1, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt or N-oxide thereof, wherein: X1selected from N and CR2a; R1is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; R2, R2a, R3, and R4are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; and R5a, R5b, R6a, R6b, R7a, and R7b, are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene.

3. The compound of claim 1, wherein the compound of Formula (I) is selected fromor a pharmaceutically acceptable salt thereof.

4. A compound of Formula (Ia):or a pharmaceutically acceptable salt thereof, wherein: R1and R2are each independently selected from C1-3haloalkyl, CN, and Cy1; each Cy1is selected from furanyl and phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene; provided that only one of R1and R2is Cy1; L1is C(=O)NH or L1is ablsent; R4is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; and R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO- C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino.

5. The compound of claim 4, selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

6. The compound of claim 4, selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

7. A compound of Formula (Ib):or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and R2a; L1is NHC(=O) or L1is absent; L2is NHC(=O) or L2is absent; R1and R2are each independently a furanyl, optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene; R4is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; andR2a, R3, and R5are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO- C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino.

8. The compound of claim 7, having any one of the following formulae: or a pharmaceutically acceptable salt thereof.

9. The compound of claim 7, selected form any one of the following compounds:

10. A compound of Formula (Ic):or a pharmaceutically acceptable salt or N-oxide thereof, wherein: R1and R2are each independently a phenyl, optionally substituted with 1, 2, or 3 independently selected RCy1; each RCy1is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, and HO-C1-3alkylene; R4is C1-6alkyl, optionally substituted with C1-6alkoxy or C1-6alkylamino; and R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO- C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino.

11. The compound of claim 10, selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

12. A compound selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

13. A compound selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

14. A compound selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

15. A compound of Formula (III): R R2bR1bO R1aor a pharmaceutically acceptable salt thereof, wherein: Ra1is selected from H and C1-3alkyl; ring A is selected from imidazolidinone, piperazine, imidazole, oxazolidinone, thiazole, and oxazole, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O), CH2, and NH; or L1is absent; R1b, R2b, R3b, and R4bare each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R3cis halo; R4cis halo; andR1c, R2c, and R5care each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

16. The compound of claim 15, wherein ring A is selected from any one of the following moieties:wherein either indicates a point of attachment to L1.

17. The compound of claim 15 or 16, having formula:, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 15, wherein the compound is selected from any one of the following compounds:o19. A compound of Formula (IV): R4R3R2X1or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR1; R1is selected from H, ORNand N(RN)2; R2, R3, R4, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, NHC(=O)C1-6alkyl, C(=O)NHC1-6alkyl, and C(=O)NH2; wherein if X1is N, then R2and R4are not both CH3; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, and -O(CH2)n- , wherein n is 1 or 2; each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene;each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A method for treating prostate cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, provided that the compound selectively inhibits and / or degrades AR polypeptide within the mammal.

22. The method of claim 21, wherein said prostate cancer is responsive to degradation of AR polypeptide or inhibition of activity of AR polypeptide.

23. The method of claim 21, wherein the AR polypeptide comprises an ARv7 isoform.

24. The method of any one of claims 21-23, wherein the mammal is human.

25. The method of claim 24, wherein the human is male.

26. A method for treating breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, provided that: (i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal.

27. The method of claim 26, wherein said breast cancer is responsive to degradation or inhibition of activity of ER polypeptide, or responsive to degradation or inhibition of activity or ER polypeptide and AR polypeptide.

28. The method of claim 26, wherein the AR polypeptide comprises an ARv7 isoform.

29. The method of any one of claims 26-28, wherein the mammal is human.

30. The method of claim 29, wherein the human is female.

31. A method of treating prostate cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of Formula (Id):or a pharmaceutically acceptable salt thereof,provided that the compound selectively inhibits and / or degrades AR polypeptide within the mammal, wherein: X1is selected from N and CR1a; X2is selected from N and CR2a; X3is selected from N and CR3; provided that at least one of X1, X2, and X3is N; R1a, Ro, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRc1Rd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7; each R7is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; each RCy1is independently selected from halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl ,4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8; each R8is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1,NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; R1and R2are each independently selected from R9and S(O)2R9; each R9is independently selected from CN, C1-6haloalkyl, and Cy2; each Cy2is independently selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; each R10is independently selected from halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11; each R11is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; each Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and each Rgis independently selected from OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, (C=O)C6-10aryl, (C=O)C3-10cycloalkyl, (C=O)5-10 membered heteroaryl, (C=O)4-10 membered heterocycloalkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

32. A method of treating breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of Formula (Id):or a pharmaceutically acceptable salt thereof,provided that: (i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal, wherein: X1is selected from N and CR1a; X2is selected from N and CR2a; X3is selected from N and CR3; provided that at least one of X1, X2, and X3is N; R1a, Ro, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRc1Rd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7; each R7is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; each RCy1is independently selected from halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl ,4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8;each R8is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; R1and R2are each independently selected from R9and S(O)2R9; each R9is independently selected from CN, C1-6haloalkyl, and Cy2; each Cy2is independently selected from C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; each R10is independently selected from halo, CN, NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11; each R11is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; each Ra1, Rb1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and each Rgis independently selected from OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, (C=O)C6-10aryl, (C=O)C3-10cycloalkyl, (C=O)5-10 membered heteroaryl, (C=O)4-10 membered heterocycloalkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

33. The method of claim 31 or 32, wherein the compound has formula:or a pharmaceutically acceptable salt thereof.

34. The method of claim 31 or 32, wherein the compound has formula:, or a pharmaceutically acceptable salt thereof.

35. The method of claim 31 or 32, wherein the compound has formula:, or a pharmaceutically acceptable salt thereof.

36. The method of claim 31 or 32, wherein the compound has formula:, or a pharmaceutically acceptable salt thereof.

37. The method of claim 31 or 32, wherein the compound is selected from any one of the following compounds:

38. A method of treating prostate cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of Formula (II):or a pharmaceutically acceptable salt or N-oxide thereof, provided that the compound selectively inhibits and / or degrades AR polypeptide within the mammal, wherein: X1is selected from N and CR4a; X2is selected from C(=O), CHOH, CH2, NRNC(=O), C(=O)NRN, and NRN; RNis selected from H and C1-3alkyl; and R1, R2, R3, R4, R4a, R5, R6, R7, and R8are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano- C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino.

39. A method of treating breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of Formula (II):or a pharmaceutically acceptable salt thereof, provided that: (i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal, wherein: X1is selected from N and CR4a; X2is selected from C(=O), CHOH, CH2, NRNC(=O), C(=O)NRN, and NRN; RNis selected from H and C1-3alkyl; and R1, R2, R3, R4, R4a, R5, R6, R7, and R8are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano- C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino.

40. The method of claim 38 or 39, wherein the compound of Formula (II) has formula:, or a pharmaceutically acceptable salt thereof.

41. The method of claim 38 or 39, wherein the compound of Formula (II) is selectedor a pharmaceutically acceptable salt thereof.

42. A method of treating prostate cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, provided that the compound selectively inhibits and / or degrades AR polypeptide within the mammal, wherein: X1is selected from N and CR1; R1is selected from H, ORNand N(RN)2; R2, R3, R4, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, NHC(=O)C1-6alkyl, C(=O)NHC1-6alkyl, and C(=O)NH2; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, and -O(CH2)n- , wherein n is 1 or 2; each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3 alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6 alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

43. A method of treating breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, provided that: (i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal, wherein: X1is selected from N and CR1; R1is selected from H, ORNand N(RN)2; R2, R3, R4, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, NHC(=O)C1-6alkyl, C(=O)NHC1-6alkyl, and C(=O)NH2; ; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, and -O(CH2)n- , wherein n is 1 or 2; each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3 alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6 alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy. 4 The method of claim 42 or 43, wherein the compound of Formula (IV) is selected from any one of the following formulae: R3R2andor a pharmaceutically acceptable salt thereof.

45. The method of claim 42 or 43, wherein the compound of Formula (IV) is selected from any one of the following formulae:or a pharmaceutically acceptable salt thereof.

46. The method of claim 42 or 43, wherein the compound of Formula (IV) is selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

47. A method of treating prostate cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof, provided that the compound selectively inhibits and / or degrades AR48. A method of treating breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof, provided that(i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal:

49. A compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein: R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

50. A compound of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein: R2, R3, R5, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

51. A compound of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR3; X2is selected from N and CR4; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4- 10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

52. A compound of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR2; X2is selected from N and CR3; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

53. A compound of Formula (IX):or a pharmaceutically acceptable salt thereof, wherein: R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, NHC(=O)C1-6alkyl, C(=O)NHC1-6alkyl, and C(=O)NH2; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4- 10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, L2-Cy2, and L2-Cy2-C1-3alkylene; L2is absent or NRN, andCy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

54. A compound of Formula (X): seor a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR1; each R1is independently selected from H, ORN, N(RN)2, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, -O(CH2)n- , C(=O)NRN-(CH2)n-, and NRNC(=O)-(CH2)n-, wherein n is 1 or 2; each R8is independently selected from OH, N(R13)2NO2, CN, C2-3alkynyl optionally substituted with amido, halo, C1-6alkyl optionally substituted with C1-2- sulfonyl, C1-6alkyl optionally substituted with C1-2-sulfonylamino, C1-6alkyl optionally substituted with C1-C3-acyl, C1-4haloalkyl, C1-6alkoxy optionally substituted with C1-2- sulfonyl, C1-6alkoxy optionally substituted with C1-2-sulfonylamino, C1-6alkoxy optionally substituted with C1-C3-acyl,, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C3-10cycloalkyloxy, 4-10 membered heterocycloalkyloxy optionally substituted with C1-6alkyl, C1-2-sulfonyl, or C1-3-acyl; C3-10cycloalkylamino, 4-10 membered heterocycloalkylamino, C1-6haloalkoxy, C1-6hydroxyalkoxy, N(R13)2-C1-6alkoxy optionally substituted with R12, N(R13)2-C1-6alkyl optionally substituted with R12,, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, , awherein each R12is independently selected from C1-2-sulfonyl, C1-3-acyl, C1-3- acylamido, C1-3haloacylamido, ureido, C1-2-sulfonylamino and aminocarbonyl; wherein each R13is independently selected from H and C1-6alkyl; or two R8groups taken together form =O, or two R8groups taken together with the atoms connecting them form a 5- or 6- membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring has one or more ring heteroatoms independently selected from the group consisting of O, S and N. each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; ring A is selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; L2is absent or is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, -(CH2)nO-, -O(CH2)n- , and -(CH2)n-, i wherein n is 1 or 2; and ring B is selected from C6-10aryl, C3-10cycloalkyl, C3-10cycloalkenyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8.

55. A pharmaceutical composition comprising a compound of any one of claims 49- 54, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

56. A method for treating prostate cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of any one of claims 49-54, or a pharmaceutically acceptable salt thereof,provided that the compound selectively inhibits and / or degrades AR polypeptide within the mammal.

57. The method of claim 56, wherein said prostate cancer is responsive to degradation of AR polypeptide or inhibition of activity of AR polypeptide.

58. The method of claim 57, wherein the AR polypeptide comprises an ARv7 isoform.

59. The method of any one of claims 56-58, wherein the mammal is human.

60. The method of claim 59, wherein the human is male.

61. A method for treating breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of any one of claims 48-52, or a pharmaceutically acceptable salt thereof, provided that: (i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal.

62. The method of claim 61, wherein said breast cancer is responsive to degradation or inhibition of activity of ER polypeptide, or responsive to degradation or inhibition of activity or ER polypeptide and AR polypeptide.

63. The method of claim 62, wherein the AR polypeptide comprises an ARv7 isoform.

64. The method of any one of claims 61-63, wherein the mammal is human.

65. The method of claim 64, wherein the human is female.

66. A compound of Formula (VIIa): (VIor a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR3; X2is selected from N and CR4; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; and each Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

67. A compound of Formula (VIIIa):(VIIIa) or a pharmaceutically acceptable salt thereof, wherein: X1is selected from N and CR2; X2is selected from N and CR3; R2, R3, R4, and R6are each independently selected from H, OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, and di(C1-6alkyl)amino; L1is selected from C(=O)NRN, NRNC(=O), C(=O), NRN, S(=O)2NRN, NRNS(=O)2, NRNC(=O)NRN, NRNS(=O)2NRN, CH2NRN, NRNCH2, and 4-10 membered heterocycloalkylene, each RNis independently selected from H, C1-3alkyl, C1-3haloalkyl, C(=O)C1-3alkyl, C(=O)C6-10aryl, S(=O)2C1-3alkyl, and S(=O)2C6-10aryl, wherein each of said C1-3alkyl and C6-10aryl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; R7is selected from Cy1and Cy1-C1-3alkylene; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R8; each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, Cy2, Cy2-C1-3alkylene; andeach Cy2is independently selected from C6-10aryl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, or carboxy.

68. A compound of Formula (XII):or a pharmaceutically acceptable salt thereof, wherein, in Formula (XII): p is 1, 2, 3, 4 or 5; each R1is independently selected from H, ORN, N(RN)2, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, and 5-10-membered heteroaryl ring having one or more ring heteroatoms selected from the group consisting of O, S and N, wherein the 5-10-membered heteroaryl ring is optionally substituted with halo or wtih C1-6alkyl; m is 0, 1 or 2; W is C1-2alkylene or C2-alkenylene, wherein W is optionallly substitued with C1-3alkyl; wherein each C1-3alkyl is optionally substituted with 1 or 2 independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; Het is a 5-membered heteroaryl ring having one or more ring heteroatoms selected from the group consisting of O, S and N; o is 0, 1, 2, 3 or 4; and each R8is independently selected from NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, and carboxy;or two R8groups taken together with the atoms connecting them form a 5- or 6- membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring has one or more ring heteroatoms selected from the group consisting of O, S and N.

69. A method of treating prostate cancer or breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of claim 66.

70. A method of treating prostate cancer or breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of claim 67.

71. A method of treating prostate cancer or breast cancer in a mammal, wherein said method comprises administering, to said mammal in need of said treatment, a compound of claim 68.

72. The method of claim 69, 70 or 71, wherein the breast cancer is responsive to degradation or inhibition of activity of ER polypeptide, or responsive to degradation or inhibition of activity or ER polypeptide and AR polypeptide.

73. The method of claim 69, 70 or 71, wherein the prostate cancer is responsive to degradation of AR polypeptide or inhibition of activity of AR polypeptide.

74. The method of claim 69, 70 or 71, wherein the cancer is breast cancer and (i) the compound selectively inhibits and / or degrades ER polypeptide within the mammal; and / or (ii) the compound inhibits and / or degrades ER polypeptide and AR polypeptide within the mammal.

75. The method of claim 69, 70 or 71, wherein the cancer is prostate cancer and the compound selectively inhibits and / or degrades AR polypeptide within the mammal.

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